A Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Retosiban (GSK221149) When Dosed With Efavirenz (EFZ)

• ClinicalTrials.gov Identifier: NCT01867996
• Recruitment Status: Completed
• First Posted: June 4, 2013
• Last Update Posted: May 11, 2017
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

This will be a randomized single sequence open label study. This study is designed to determine if chronic dosing with efavirenz (EFZ) will have an effect on the pharmacokinetics (PK) of intravenously-administered retosiban in healthy volunteers. The study consists of screening (28 days), treatment (1 dosing session) and follow-up (7 to 14 days) period, and the total duration of study participation for each subject will be approximately 8 weeks. During the treatment period, subjects will be admitted to the clinical research unit the day before dosing (Day 1) and will remain until completion of the last assessment on Day 20. All subjects will receive on Day 1, a 6 milligrams (mg) bolus of retosiban for 5 minutes (min), followed by a 6 mg/hour (hr) infusion for 12 hrs. On Day 2, a washout day will occur. On Days 3-17, subjects will receive EFZ 600 mg once daily in the evening. On Day 18, subjects will receive a 6 mg bolus of retosiban for 5 mins, followed by a 6 mg/hr infusion for 12 hrs plus a 600 mg dose of EFZ.

Condition or disease	Intervention/treatment	Phase
Obstetric Labour, Premature	Drug: Retosiban; Drug: EFZ 600 mg	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: To Evaluate the Pharmacokinetics, Safety and Tolerability of Retosiban (GSK221149) Co-administered With EFAVIRENZ
• Actual Study Start Date: June 11, 2013
• Actual Primary Completion Date: September 26, 2013
• Actual Study Completion Date: September 26, 2013

Arms and Interventions

Arm

Intervention/treatment

Experimental: Retosiban and EFZ; All subjects will receive on Day 1, a 6 mg bolus of retosiban for 5 min, followed by a 6 mg/hr infusion for 12 hrs. On Day 2 a washout day will occur. On Days 3-17, subjects will receive EFZ 600 mg OD dose of in the evening. On Day 18, subjects will receive a 6 mg bolus of retosiban for 5 mins, followed by a 6 mg/hr infusion for 12 hrs plus a 600 mg dose of EFZ.

Drug: Retosiban; Retosiban will be supplied as clear colorless solution for infusion (300 mg in 20 mL via). Subject will receive loading dose of 6 mg over 5 min infusion followed by 6 mg/hour infusion for 12 hrs on Day 1 and Day 18.; Drug: EFZ 600 mg; EZF 600 mg will be supplied as a yellow, capsular-shaped, film-coated tablet. Subjects will receive EFZ 600mg OD in the evening from Day 3 till Day 18.

Outcome Measures

Primary Outcome Measures :

1. Plasma GSK221149 (parent) and GSK2847065 (metabolite) PK parameters of AUC, Cmax and CL. [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours (hrs) after the start of the infusion on Day 1 and Day 18. ]
   The following PK parameters will be determined after administration of GSK221149 with and without EFZ 600 mg: Area under the plasma concentration-time curve (AUC)- from time zero to time t [AUC(0-t)] and from time zero extrapolated to infinite time [AUC(0-infinity)], maximum observed plasma concentration (Cmax) and clearance (CL). CL will be calculated for parent only.

Secondary Outcome Measures :

1. Safety and tolerability of administration of GSK221149 with and without EFZ 600 mg as assessed by adverse event, concurrent medication review, clinical laboratory tests, ECG, and vital signs measurements. [ Time Frame: Up to 8 Weeks ]
   Clinical laboratory tests will include hematology, clinical chemistry and urinalysis parameters. Triplicate 12-lead ECGs will be obtained at the screening visit. Single 12-lead ECGs will be obtained at other time points during the study. Vital sign measurements will include systolic and diastolic blood pressure and pulse rate.
2. Plasma GSK221149 and GSK2847065 PK parameters of tmax, tlag and t1/2. [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours (hrs) after the start of the infusion on Day 1 and Day 18. ]
   The following PK parameters will be determined after administration of GSK221149 with and without EFZ 600 mg: time to Cmax (tmax), lag time (tlag), and terminal phase half-life (t1/2). The terminal half-life (t1/2) is defined as the time required for the plasma concentration of drug to reach half of its original concentration.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Male/females aged between 18 and 45 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 cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator in consultation with the GlaxoSmithKline (GSK) Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Body weight >=50 kilogram (kg) and body mass index within the range 19-29.9 kg/m^2.
• A female subject is eligible to participate if she is of: Child-bearing potential with negative pregnancy test as determined by serum human chorionic gonadotrophin (hCG) test at screening or prior to dosing; AND Agrees to use 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 follow-up visit; OR 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
• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <=1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Based on averaged corrected QT interval (QTc) values of triplicate electrocardiograms obtained over a brief recording period: QTc < 450 milliseconds (msec); or QTc < 480 msec in subjects with Bundle Branch Block.

Exclusion Criteria:

• 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: For United States (US) sites: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram of alcohol: 12 ounces (360 milliliter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• History of sensitivity to any of the study medications, 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.
• Has active suicidal plan/intent or has had active suicidal thoughts in the past 6 months. Has history of suicide attempt in the last 2 years or more than 1 lifetime suicide attempt.
• Subjects with a history of seizures will be excluded from this trial.
• Subjects with a history of severe or serious psychiatric disease requiring hospitalization, history of social ideation or attempt, or on ongoing psychiatric treatment will be excluded from this study.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• A positive pre-study drug/alcohol screen.
• A positive test for Human Immunodeficiency Virus (HIV) antibody.
• Pregnant females as determined by positive serum hCG test at screening or prior to dosing.
• 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.

Contacts and Locations

Locations

United States, Maryland

GSK Investigational Site

Baltimore, Maryland, United States, 21225

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

Additional Information:

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research. 

Study Data/Documents: Annotated Case Report Form 

Identifier: 116073
For additional information about this study please refer to the GSK Clinical Study Register

Informed Consent Form 

Identifier: 116073
For additional information about this study please refer to the GSK Clinical Study Register

Clinical Study Report 

Identifier: 116073
For additional information about this study please refer to the GSK Clinical Study Register

Individual Participant Data Set 

Identifier: 116073
For additional information about this study please refer to the GSK Clinical Study Register

Dataset Specification 

Identifier: 116073
For additional information about this study please refer to the GSK Clinical Study Register

Study Protocol 

Identifier: 116073
For additional information about this study please refer to the GSK Clinical Study Register

Statistical Analysis Plan 

Identifier: 116073
For additional information about this study please refer to the GSK Clinical Study Register

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01867996
• Other Study ID Numbers: 116073
• First Posted: June 4, 2013
• Last Update Posted: May 11, 2017
• Last Verified: May 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.

Keywords provided by GlaxoSmithKline:

Retosiban, Efavirenz, Induction

Additional relevant MeSH terms:

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications