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Effect of Rifabutin on the Pharmacokinetics of Oral Cabotegravir in Healthy Subjects

Primary Purpose

Infection, Human Immunodeficiency Virus, HIV Infections

Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Cabotegravir
Rifabutin
Sponsored by
ViiV Healthcare
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infection, Human Immunodeficiency Virus focused on measuring Tuberculosis, Human Immunodeficiency Virus, Rifabutin, Drug-drug interaction, Cabotegravir

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria

  • Males and females between 18 and 65 years of age inclusive, at the time of signing the informed consent.
  • Healthy as determined by the investigator or medically qualified designee 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 Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Additionally, laboratory assessments that are specifically listed in the inclusion or exclusion criteria and are outside of the reference range can be repeated once during the screening period.
  • Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 18.5 - 31.0 kg/ meter square (kg/m^2) (inclusive).
  • A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test), not lactating, and if she is of:

    • Non-reproductive potential defined as pre-menopausal with documented tubal ligation, hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Bilateral Oophorectomy, Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause FSH: >40 milli international unit/mililiter (MIU/mL) and estradiol <40 picogram (pg)/mL (<147 picomoles/L) is confirmatory];
    • Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication until the completion of the follow-up visit.

The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
  • ALT, alkaline phosphatase and bilirubin <=1x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • White blood cell count and absolute neutrophil count in the normal range.

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 clinically significant cardiovascular disease including

    • Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): male subjects with heart rate <45 and >100 beats per minute (bpm) and female subjects with heart rate <50 and >100 bpm, QRS duration (males and females) >120 millisecond (msec), QTc corrected by Fridericia's formula (QTcF) >450 msec for males and females.
    • Evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes (except early repolarization).
    • History/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PCTA) or any clinically significant cardiac disease.
    • Conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree (type II) or higher], Wolf Parkinson White [WPW] syndrome) which in the opinion of the principal Investigator and Viiv Medical Monitor, will interfere with the safety for the individual subject.
    • Sinus pauses >3 seconds.
    • Any significant arrhythmia which, in the opinion of the principal Investigator and ViiV Medical Monitor, will interfere with the safety for the individual subject.
    • Non-sustained (>=3 consecutive ventricular ectopic beats) or sustained ventricular tachycardia.
  • History of inflammatory bowel disease.
  • History of cholecystectomy or other gastrointestinal surgery (except appendectomy more than three months prior to study).
  • History of peptic ulceration or pancreatitis within the preceding 6 months of screening.
  • Participants determined by the Investigator to have a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder. A participant with a prior history of seizure may be considered for enrolment if the Investigator believes the risk of seizure recurrence is low. All cases of prior seizure history should be discussed with the Medical Monitor prior to enrolment.
  • Current or past history of uveitis.
  • Any other medical condition which, in the judgment of the investigator and medical monitor, could jeopardize the safety of the subject or the integrity of the data derived from that subject. This includes but is not limited to any pre-existing condition that interferes with normal gastrointestinal anatomy or motility that could interfere with the absorption, metabolism, and/or excretion of the study drug.
  • 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 ViiV Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks. One drink is equivalent to 12 gram 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.
  • A history of regular use of tobacco, or nicotine-containing products within 30 days prior to screening.
  • 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 Medical Monitor, contraindicates their participation.
  • Presence of Hepatitis B surface antigen (HBsAg) positivity at screening or within 3 months prior to first dose of study treatment. Positive Hepatitis B core antibody (HBcAb) with negative hepatitis B surface antibody should also be excluded.
  • Positive Hepatitis C antibody test.
  • A positive pre-study drug/alcohol screen.
  • A positive test for HIV antibody.
  • A positive QuantiFERON Gold test or clinical evidence of tuberculosis (TB) infection.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  • 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.

Sites / Locations

  • GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Treatment A

Treatment B

Arm Description

Participants will be administered a single oral dose of CAB 30 mg after an overnight fast of at least 6 hours for 14 days in Period 1. Dosing of study medication on non-PK days may be with or without food.

Participants will be administered a single dose of RBT 300 mg and a single dose of CAB 30 mg after an overnight fast of at least 6 hours once daily for 14 days in Period 2. Dosing of study medication on non-PK days may be with or without food.

Outcomes

Primary Outcome Measures

Assessment of Plasma CAB Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over One Dosing Interval (AUC [0 to Tau])
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. AUC (0 to tau) was calculated using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. PK Summary Population included participants who had CAB PK parameter estimates from both serial PK sampling time periods 1 and 2. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.
Assessment of Plasma CAB PK Parameter: Maximum Observed Concentration (Cmax)
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Cmax was determined directly from the concentration-time data. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.

Secondary Outcome Measures

Assessment of Plasma CAB PK Parameter: Concentration at the End of the Dosing Interval (Ctau)
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.
Assessment of Plasma CAB PK Parameter: Time of Occurrence of Cmax (Tmax)
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Tmax was determined directly from the concentration-time data.
Assessment of Plasma CAB PK Parameter: Terminal Phase Half-life (t1/2)
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Apparent terminal half-life was calculated as: t1/2 = ln2 / Lambda_z, where Lambda_z is the terminal phase rate constant. Plasma t1/2 was not estimated for either period due to limited PK sampling in the terminal phase.
Assessment of Plasma CAB PK Parameter: The Apparent Oral Clearance (CL/F)
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. CL/F was calculated as CL/F =Dose/AUC(0 to tau).
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect and associated with liver injury and impaired liver function. Safety Population comprised of all participants who enrolled in the study and received at least one dose of study drug.
Concurrent Medication Assessment in Treatment Period 1 and 2
Concurrent medications included paracetamol and ibuprofen. Number of participants who took concurrent medications during the study are presented.
Assessment of Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes
Blood samples for hematology assessment were collected for basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameters: Hematocrit and Reticulocytes/Erythrocytes (R/E)
Blood samples for hematology assessment were collected for Hematocrit and R/E. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameter: Hemoglobin
Blood samples for hematology assessment was collected for Hemoglobin. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameter: Eryrocyte Mean Corpuscular Hemoglobin
Blood samples for hematology assessment was collected for Eryrocyte Mean Corpuscular Hemoglobin. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameter: Erythrocye Mean Corpuscular Volume
Blood samples for hematology assessment was collected for Erythrocyte Mean Corpuscular Volume. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameters: Erythrocytes and Reticulocytes
Blood samples for hematology assessment were collected for Erythrocytes and reticulocytes. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameters: Erythrocytes Distribution Width (EDW)
Blood samples for hematology assessment was collected for EDW. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Clinical Chemistry Parameters: Albumin and Protein
Samples for clinical chemistry assessment were collected for Albumin and Protein. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT)
Samples for clinical chemistry assessment were collected for ALP, AST, ALT, CK and GGT. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Clinical Chemistry Parameters: Direct Bilirubin (DB), Bilirubin and Creatinine
Samples for clinical chemistry assessment were collected for DB, bilirubin and creatinine. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Clinical Chemistry Parameters: Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium and Urea
Samples for clinical chemistry assessment were collected for Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium and Urea. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Number of Participants With Abnormal Urinalysis Result
Samples for urinalysis assessment was collected at Day -1, Day 13, Day 21, Day 27 and during follow-up period (10 to 14 daya after last dose). Data for participants with abnormal urinalysis results has been presented.
Number of Participants With Abnormal Electrocardiogram (ECG) Findings
ECG measurements was performed with the participant in a semi-supine position having rested in this position for at least 10 minutes beforehand. Data has been presented for Period 1, Day 14 pre-dose which showed abnormal- not clinically significant ECG finding. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Vital signs measurement was done in semi-supine position after 10 minutes rest and included SBP and DBP. Two blood pressure measurement were taken at pre-dose on Day 1, at least 1 minute apart. The mean value recorded at pre-dose was classified as Baseline. Single blood pressure was obtained at all other time points during the study. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Change From Baseline in Pulse Rate
Vital signs measurement was done in semi-supine position after 10 minutes rest and included pulse rate. Two pulse rate measurement were taken at pre-dose on Day 1, at least 1 minute apart. The mean value recorded at pre-dose was classified as Baseline. Single pulse rate was obtained at all other time points during the study. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Full Information

First Posted
May 9, 2017
Last Updated
August 27, 2020
Sponsor
ViiV Healthcare
Collaborators
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT03149848
Brief Title
Effect of Rifabutin on the Pharmacokinetics of Oral Cabotegravir in Healthy Subjects
Official Title
Phase I, Single-center, Open Label, Fixed-sequence Cross-over Study to Evaluate the Effect of Rifabutin on the Pharmacokinetics of Oral Cabotegravir in Healthy Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
June 6, 2017 (Actual)
Primary Completion Date
September 6, 2017 (Actual)
Study Completion Date
September 7, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ViiV Healthcare
Collaborators
GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a Phase I, single-center, open-label, fixed-sequence, 2-period crossover study in healthy adults to evaluate the effect of oral rifabutin (RBT) 300 milligram (mg) on the pharmacokinetics of oral cabotegravir (CAB) 30 milligram ( mg). This study will evaluate the drug-drug interaction (DDI) potential between CAB and RBT to inform dosing strategies for tuberculosis in subjects receiving CAB for human immunodeficiency virus (HIV) treatment or prevention. In Treatment Period 1 (Treatment A) participants will receive CAB 30 mg once daily for 14 days, followed by Treatment Period 2 (Treatment B) where participants will receive RBT 300 mg once daily with CAB 30 mg once daily for 14 days. The total study duration will be approximately for 10 weeks. Approximately 15 healthy subjects will be enrolled to ensure that 12 subjects complete dosing and critical assessments.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infection, Human Immunodeficiency Virus, HIV Infections
Keywords
Tuberculosis, Human Immunodeficiency Virus, Rifabutin, Drug-drug interaction, Cabotegravir

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Model Description
This is a 2-period crossover study in healthy adults
Masking
None (Open Label)
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment A
Arm Type
Experimental
Arm Description
Participants will be administered a single oral dose of CAB 30 mg after an overnight fast of at least 6 hours for 14 days in Period 1. Dosing of study medication on non-PK days may be with or without food.
Arm Title
Treatment B
Arm Type
Experimental
Arm Description
Participants will be administered a single dose of RBT 300 mg and a single dose of CAB 30 mg after an overnight fast of at least 6 hours once daily for 14 days in Period 2. Dosing of study medication on non-PK days may be with or without food.
Intervention Type
Drug
Intervention Name(s)
Cabotegravir
Intervention Description
It will be available as a white aquarius film coated tablet for oral administration. CAB Tablet is composed of GSK1265744B (micronized) lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate
Intervention Type
Drug
Intervention Name(s)
Rifabutin
Intervention Description
It will be available as an opaque red-brown hard gelatin capsules containing 150 mg of rifabutin for oral administration. These capsules are composed of rifabutin, microcrystalline cellulose, sodium lauryl sulphate, magnesium stearate, and silica gel
Primary Outcome Measure Information:
Title
Assessment of Plasma CAB Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over One Dosing Interval (AUC [0 to Tau])
Description
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. AUC (0 to tau) was calculated using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. PK Summary Population included participants who had CAB PK parameter estimates from both serial PK sampling time periods 1 and 2. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.
Time Frame
Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28
Title
Assessment of Plasma CAB PK Parameter: Maximum Observed Concentration (Cmax)
Description
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Cmax was determined directly from the concentration-time data. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.
Time Frame
Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28
Secondary Outcome Measure Information:
Title
Assessment of Plasma CAB PK Parameter: Concentration at the End of the Dosing Interval (Ctau)
Description
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.
Time Frame
Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28
Title
Assessment of Plasma CAB PK Parameter: Time of Occurrence of Cmax (Tmax)
Description
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Tmax was determined directly from the concentration-time data.
Time Frame
Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28
Title
Assessment of Plasma CAB PK Parameter: Terminal Phase Half-life (t1/2)
Description
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Apparent terminal half-life was calculated as: t1/2 = ln2 / Lambda_z, where Lambda_z is the terminal phase rate constant. Plasma t1/2 was not estimated for either period due to limited PK sampling in the terminal phase.
Time Frame
Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28
Title
Assessment of Plasma CAB PK Parameter: The Apparent Oral Clearance (CL/F)
Description
Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. CL/F was calculated as CL/F =Dose/AUC(0 to tau).
Time Frame
Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect and associated with liver injury and impaired liver function. Safety Population comprised of all participants who enrolled in the study and received at least one dose of study drug.
Time Frame
Up to 10 weeks
Title
Concurrent Medication Assessment in Treatment Period 1 and 2
Description
Concurrent medications included paracetamol and ibuprofen. Number of participants who took concurrent medications during the study are presented.
Time Frame
Up to 10 weeks
Title
Assessment of Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes
Description
Blood samples for hematology assessment were collected for basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Hematology Parameters: Hematocrit and Reticulocytes/Erythrocytes (R/E)
Description
Blood samples for hematology assessment were collected for Hematocrit and R/E. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Hematology Parameter: Hemoglobin
Description
Blood samples for hematology assessment was collected for Hemoglobin. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Hematology Parameter: Eryrocyte Mean Corpuscular Hemoglobin
Description
Blood samples for hematology assessment was collected for Eryrocyte Mean Corpuscular Hemoglobin. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Hematology Parameter: Erythrocye Mean Corpuscular Volume
Description
Blood samples for hematology assessment was collected for Erythrocyte Mean Corpuscular Volume. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Hematology Parameters: Erythrocytes and Reticulocytes
Description
Blood samples for hematology assessment were collected for Erythrocytes and reticulocytes. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Hematology Parameters: Erythrocytes Distribution Width (EDW)
Description
Blood samples for hematology assessment was collected for EDW. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Clinical Chemistry Parameters: Albumin and Protein
Description
Samples for clinical chemistry assessment were collected for Albumin and Protein. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT)
Description
Samples for clinical chemistry assessment were collected for ALP, AST, ALT, CK and GGT. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Clinical Chemistry Parameters: Direct Bilirubin (DB), Bilirubin and Creatinine
Description
Samples for clinical chemistry assessment were collected for DB, bilirubin and creatinine. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Assessment of Clinical Chemistry Parameters: Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium and Urea
Description
Samples for clinical chemistry assessment were collected for Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium and Urea. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Number of Participants With Abnormal Urinalysis Result
Description
Samples for urinalysis assessment was collected at Day -1, Day 13, Day 21, Day 27 and during follow-up period (10 to 14 daya after last dose). Data for participants with abnormal urinalysis results has been presented.
Time Frame
Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
Title
Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Description
ECG measurements was performed with the participant in a semi-supine position having rested in this position for at least 10 minutes beforehand. Data has been presented for Period 1, Day 14 pre-dose which showed abnormal- not clinically significant ECG finding. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Day 1, 14, 21, 28 and follow-up (10 to 14 days after last dose)
Title
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Description
Vital signs measurement was done in semi-supine position after 10 minutes rest and included SBP and DBP. Two blood pressure measurement were taken at pre-dose on Day 1, at least 1 minute apart. The mean value recorded at pre-dose was classified as Baseline. Single blood pressure was obtained at all other time points during the study. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Baseline to follow-up (10 to 14 days after last dose)
Title
Change From Baseline in Pulse Rate
Description
Vital signs measurement was done in semi-supine position after 10 minutes rest and included pulse rate. Two pulse rate measurement were taken at pre-dose on Day 1, at least 1 minute apart. The mean value recorded at pre-dose was classified as Baseline. Single pulse rate was obtained at all other time points during the study. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Time Frame
Baseline to follow-up (10 to 14 days after last dose)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria Males and females between 18 and 65 years of age inclusive, at the time of signing the informed consent. Healthy as determined by the investigator or medically qualified designee 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 Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Additionally, laboratory assessments that are specifically listed in the inclusion or exclusion criteria and are outside of the reference range can be repeated once during the screening period. Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 18.5 - 31.0 kg/ meter square (kg/m^2) (inclusive). A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test), not lactating, and if she is of: Non-reproductive potential defined as pre-menopausal with documented tubal ligation, hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Bilateral Oophorectomy, Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause FSH: >40 milli international unit/mililiter (MIU/mL) and estradiol <40 picogram (pg)/mL (<147 picomoles/L) is confirmatory]; Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication until the completion of the follow-up visit. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. ALT, alkaline phosphatase and bilirubin <=1x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). White blood cell count and absolute neutrophil count in the normal range. 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 clinically significant cardiovascular disease including Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): male subjects with heart rate <45 and >100 beats per minute (bpm) and female subjects with heart rate <50 and >100 bpm, QRS duration (males and females) >120 millisecond (msec), QTc corrected by Fridericia's formula (QTcF) >450 msec for males and females. Evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes (except early repolarization). History/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PCTA) or any clinically significant cardiac disease. Conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree (type II) or higher], Wolf Parkinson White [WPW] syndrome) which in the opinion of the principal Investigator and Viiv Medical Monitor, will interfere with the safety for the individual subject. Sinus pauses >3 seconds. Any significant arrhythmia which, in the opinion of the principal Investigator and ViiV Medical Monitor, will interfere with the safety for the individual subject. Non-sustained (>=3 consecutive ventricular ectopic beats) or sustained ventricular tachycardia. History of inflammatory bowel disease. History of cholecystectomy or other gastrointestinal surgery (except appendectomy more than three months prior to study). History of peptic ulceration or pancreatitis within the preceding 6 months of screening. Participants determined by the Investigator to have a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder. A participant with a prior history of seizure may be considered for enrolment if the Investigator believes the risk of seizure recurrence is low. All cases of prior seizure history should be discussed with the Medical Monitor prior to enrolment. Current or past history of uveitis. Any other medical condition which, in the judgment of the investigator and medical monitor, could jeopardize the safety of the subject or the integrity of the data derived from that subject. This includes but is not limited to any pre-existing condition that interferes with normal gastrointestinal anatomy or motility that could interfere with the absorption, metabolism, and/or excretion of the study drug. 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 ViiV Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks. One drink is equivalent to 12 gram 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. A history of regular use of tobacco, or nicotine-containing products within 30 days prior to screening. 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 Medical Monitor, contraindicates their participation. Presence of Hepatitis B surface antigen (HBsAg) positivity at screening or within 3 months prior to first dose of study treatment. Positive Hepatitis B core antibody (HBcAb) with negative hepatitis B surface antibody should also be excluded. Positive Hepatitis C antibody test. A positive pre-study drug/alcohol screen. A positive test for HIV antibody. A positive QuantiFERON Gold test or clinical evidence of tuberculosis (TB) infection. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
ViiV Healthcare
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Cambridge
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD for this study will be made available via the Clinical Study Data Request site.
IPD Sharing Time Frame
IPD is available via the Clinical Study Data Request site (click on the link provided below)
IPD Sharing Access Criteria
Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
IPD Sharing URL
https://clinicalstudydatarequest.com/Posting.aspx?ID=20363
Citations:
PubMed Identifier
30896438
Citation
Ford SL, Lou Y, Lewis N, Kostapanos M, D'Amico R, Spreen W, Patel P. Effect of rifabutin on the pharmacokinetics of oral cabotegravir in healthy subjects. Antivir Ther. 2019;24(4):301-308. doi: 10.3851/IMP3306.
Results Reference
background

Learn more about this trial

Effect of Rifabutin on the Pharmacokinetics of Oral Cabotegravir in Healthy Subjects

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