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NCT Number: NCT03149848

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

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.

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Key information

Conditions

Infection, Human Immunodeficiency Virus Acquired Immunodeficiency Syndrome Actinomycetales Infections Bacterial Infections Bacterial Infections and Mycoses Blood-Borne Infections Communicable Diseases Genital Diseases Gram-Positive Bacterial Infections HIV Infections Immune System Diseases Immunologic Deficiency Syndromes Infections Lentivirus Infections Mycobacterium Infections RNA Virus Infections Retroviridae Infections Sexually Transmitted Diseases Sexually Transmitted Diseases, Viral Slow Virus Diseases Tuberculosis Urogenital Diseases Virus Diseases

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

GSK Investigational Site

Cambridge, United Kingdom

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Cabotegravir

Drug

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

rifabutin

Drug

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 outcomes

  1. Assessment of Plasma CAB Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over One Dosing Interval (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

    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.

  2. Assessment of Plasma CAB PK Parameter: Maximum Observed Concentration (Cmax)

    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

    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 outcomes

  1. Assessment of Plasma CAB PK Parameter: Concentration at the End of the Dosing Interval (Ctau)

    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

    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.

  2. Assessment of Plasma CAB PK Parameter: Time of Occurrence of Cmax (Tmax)

    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

    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.

  3. Assessment of Plasma CAB PK Parameter: Terminal Phase Half-life (t1/2)

    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

    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.

  4. Assessment of Plasma CAB PK Parameter: The Apparent Oral Clearance (CL/F)

    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

    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).

  5. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Time frame: Up to 10 weeks

    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.

  6. Concurrent Medication Assessment in Treatment Period 1 and 2

    Time frame: Up to 10 weeks

    Concurrent medications included paracetamol and ibuprofen. Number of participants who took concurrent medications during the study are presented.

  7. Assessment of Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  8. Assessment of Hematology Parameters: Hematocrit and Reticulocytes/Erythrocytes (R/E)

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  9. Assessment of Hematology Parameter: Hemoglobin

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  10. Assessment of Hematology Parameter: Eryrocyte Mean Corpuscular Hemoglobin

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  11. Assessment of Hematology Parameter: Erythrocye Mean Corpuscular Volume

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  12. Assessment of Hematology Parameters: Erythrocytes and Reticulocytes

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  13. Assessment of Hematology Parameters: Erythrocytes Distribution Width (EDW)

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  14. Assessment of Clinical Chemistry Parameters: Albumin and Protein

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  15. Assessment of Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT)

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  16. Assessment of Clinical Chemistry Parameters: Direct Bilirubin (DB), Bilirubin and Creatinine

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  17. Assessment of Clinical Chemistry Parameters: Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium and Urea

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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).

  18. Number of Participants With Abnormal Urinalysis Result

    Time frame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)

    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.

  19. Number of Participants With Abnormal Electrocardiogram (ECG) Findings

    Time frame: Day 1, 14, 21, 28 and follow-up (10 to 14 days after last dose)

    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).

  20. Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

    Time frame: Baseline to follow-up (10 to 14 days after last dose)

    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).

  21. Change From Baseline in Pulse Rate

    Time frame: Baseline to follow-up (10 to 14 days after last dose)

    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).

Sponsors and collaborators

Lead sponsor

ViiV Healthcare

Industry

Collaborators

  • GlaxoSmithKline

Registry information

Official study 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

Important dates

Study start
2017
Primary completion
2017
Study completion
2017
First posted
May 11, 2017
Registry last updated
Sep 17, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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