Clinical trial NCT03149848: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Infection, Human Immunodeficiency Virus
HIV Infections
Keywords: Tuberculosis
Human Immunodeficiency Virus
Rifabutin
Drug-drug interaction
Cabotegravir
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2017-05-11
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a 2-period crossover study in healthy adults
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Assessment of Plasma CAB Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over One Dosing Interval (AUC [0 to Tau])
timeFrame: 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
measure: Assessment of Plasma CAB PK Parameter: Maximum Observed Concentration (Cmax)
timeFrame: 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 outcomes:
measure: Assessment of Plasma CAB PK Parameter: Concentration at the End of the Dosing Interval (Ctau)
timeFrame: 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
measure: Assessment of Plasma CAB PK Parameter: Time of Occurrence of Cmax (Tmax)
timeFrame: 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
measure: Assessment of Plasma CAB PK Parameter: Terminal Phase Half-life (t1/2)
timeFrame: 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
measure: Assessment of Plasma CAB PK Parameter: The Apparent Oral Clearance (CL/F)
timeFrame: 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
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 10 weeks
measure: Concurrent Medication Assessment in Treatment Period 1 and 2
timeFrame: Up to 10 weeks
measure: Assessment of Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Hematology Parameters: Hematocrit and Reticulocytes/Erythrocytes (R/E)
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Hematology Parameter: Hemoglobin
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Hematology Parameter: Eryrocyte Mean Corpuscular Hemoglobin
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Hematology Parameter: Erythrocye Mean Corpuscular Volume
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Hematology Parameters: Erythrocytes and Reticulocytes
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Hematology Parameters: Erythrocytes Distribution Width (EDW)
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Clinical Chemistry Parameters: Albumin and Protein
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT)
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Clinical Chemistry Parameters: Direct Bilirubin (DB), Bilirubin and Creatinine
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Assessment of Clinical Chemistry Parameters: Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium and Urea
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Number of Participants With Abnormal Urinalysis Result
timeFrame: Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose)
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Day 1, 14, 21, 28 and follow-up (10 to 14 days after last dose)
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline to follow-up (10 to 14 days after last dose)
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline to follow-up (10 to 14 days after last dose)
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
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.