Clinical trial NCT02216331: PK Interaction Between Rifapentine or Rifampicin and a Single Dose of TMC207 in Healthy Subjects (TMC207-CL002)
Official title: A Phase I Open-label Trial to Investigate the Pharmacokinetic Interaction Between Rifapentine or Rifampicin and a Single Dose of TMC207 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Tuberculosis
Keywords: tuberculosis
PK
TMC207
bedaquiline
rifapentine
rifampicin
drug drug interaction
Lead sponsor: Global Alliance for TB Drug Development
Sponsor class: OTHER
First posted: 2014-08-13
Enrollment: 32
Sex: ALL
Minimum age (years): 19
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a open-label study, 2-treatment, 2-period, single sequence design. Period 1 will examine the pharmacokinetics of TMC207 in the absence of rifapentine or rifampicin. Subjects will receive a single 400-mg dose of TMC207 administered alone on Study Day 1. Period 2 will examine the effects of repeated doses of either rifapentine or rifampicin on TMC207 pharmacokinetics and will begin on Study Day 20. During Period 2, subjects will receive 22 daily doses of either 600 mg rifapentine or rifampicin from Study Day 20 through Study Day 41. A single 400-mg dose of TMC207 will be administered on Study Day 29. Subjects will be confined to the clinic from Study Day-1 to Study Day 2 in the morning of Period 1, and Study Day 19 to Study Day 30 in the morning of Period 2. The study hypothesis is to determine whether Rifapentine affects the pharmacokinetics of TMC207 as measured by effects on Cmax and AUC(0-t) to a lesser degree than rifampicin.


Eligibility criteria: Inclusion Criteria:

* Aged between 19 and 55 years, extremes included.
* Non tobacco/nicotine using (at least 3 months prior to screening).
* Body Mass Index (BMI, weight in kg divided by the square of height in meters) of 18.0 to 32.0 kg/m2, inclusive.
* Informed Consent Form (ICF) signed voluntarily before the first trial-related activity.
* Able to comply with protocol requirements.
* Healthy on the basis of a medical evaluation or history that reveals the absence of any clinically relevant abnormality and includes a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry, and hematology tests and a urinalysis carried out at screening (See Section 6.1).

Exclusion Criteria:

* Female, except if postmenopausal since more than 2 years, or post-hysterectomy, or post surgical sterilization, i.e., tubal ligation (without reversal operation) or total hysterectomy.
* History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use, which in the investigator's opinion would compromise subject's safety and/or compliance with the trial procedures.
* Any clinically significant (as deemed by the Principle Investigator) history acute illness (resolved within 4 weeks of screening), or presence of cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal (including eating disorders), endocrine, metabolic, immunologic, dermatologic, neurologic, psychological, or psychiatric disease.
* Currently significant diarrhea, gastric stasis, or constipation that in the investigator's opinion could influence drug absorption or bioavailability.
* Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. Subjects with a history of skin disease may be enrolled into the study after consultation with the Sponsor Medical Monitor.
* Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e. rifapentine, rifampicin, and TMC207).
* Subjects with QTcF \[Fredericia correction\] interval \> 450 msec (based on the average of the triplicate ECGs) at screening (and confirmed by repeat ECG).
* Subjects with any other clinically significant ECG abnormality at screening, such as arrhythmia, ischemia, or evidence of heart failure or with a family history of Long QT Syndrome.
* Use of concomitant medication, including over-the-counter products and dietary supplements, except for ibuprofen and paracetamol up to 7 days before the first dose of trial medication and all prescribed medication must have been discontinued at least 14 days before first intake of trial medication.
* Participation in an investigational drug trial within 60 days prior to the first intake of trial medication.
* Donation of blood or significant loss of blood within 56 days or plasma donation within 7 days preceding the first intake of trial medication.
* Having received TMC207 in a previous trial.
* Positive HIV-1 or HIV-2 test at screening
* Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B surface antigen, or hepatitis C virus antibody, respectively) at screening.
* A positive urine drug test at screening. Urine will be tested to check the current use of alcohol, amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids.
* Subjects with the following laboratory abnormalities at screening as defined by the NIH, NIAID, Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table and in accordance with the normal ranges of the clinical laboratory: Serum creatinine grade 1 or greater (\> 1.0 x ULN); Pancreatic lipase grade 1 or greater (\> 1.0 x ULN); Hemoglobin grade 1 or greater (≤ 10.5 g/dL); Platelet count grade 1 or greater (≤ 99000/mm3); Absolute neutrophil count grade 1 or greater (≤ 1500/mm3); Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater (\> 1.0 x ULN); Total bilirubin grade 1 or greater (\> 1.0 x ULN); Any other toxicity grade 2 or above, including: proteinuria (spot urine) \> 1+ and gross hematuria.

Primary outcomes:
measure: Maximum observed TMC207 concentration in ng/mL [Cmax] between Groups 1 and 2
timeFrame: through 336 hours post dosing in Period 1 and Period 2
measure: Area under the TMC207 concentration-time curve in ng*hr/mL [AUC0-t] between Groups 1 and 2
timeFrame: through 336 hours post dosing in Period 1 and Period 2
measure: Area under the TMC207 concentration cuve from time zero to infinity in ng*hr/mL [AUC0-inf] between Groups 1 and 2
timeFrame: through 336 hours post dosing in Period 1 and Period 2
Secondary outcomes:
measure: Maximum observed TMC207 concentration in ng/mL [Cmax] within treatment groups between Periods 1 and 2
timeFrame: through 336 hours post dosing in Period 1 and Period 2
measure: Area under the TMC207 concentration-time curve in ng*hr/mL [AUC0-t] within treatment groups between Periods 1 and 2
timeFrame: through 336 hours post dosing in Period 1 and Period 2
measure: Area under the TMC207 concentration cuve from time zero to infinity in ng*hr/mL [AUC0-inf] within treatment groups between Periods 1 and 2
timeFrame: through 336 hours post dosing in Period 1 and Period 2
Other outcomes:
measure: Number of participants with adverse events
timeFrame: through study day 57
Locations:
city: Lincoln
country: United States
facility: Celerion (MDS Pharma Services)
state: Nebraska
Study officials:
affiliation: Celerion (MDS Pharma Services)
name: Scott Rasmussen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Winter H, Egizi E, Murray S, Erondu N, Ginsberg A, Rouse DJ, Severynse-Stevens D, Pauli E. Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects. Antimicrob Agents Chemother. 2015 Feb;59(2):1219-24. doi: 10.1128/AAC.04171-14. Epub 2014 Dec 15.