TMC207 +/- Rifabutin/Rifampin

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01341184
First received: April 7, 2011
Last updated: April 25, 2013
Last verified: February 2012
  Purpose

Evaluation of effect of rifampin or rifabutin on single dose PK of TMC207 in healthy volunteers


Condition Intervention Phase
Tuberculosis
Drug: Rifabutin
Drug: Rifampin
Drug: TMC207
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Open-Label Trial To Investigate the Pharmacokinetic Interaction Between Rifabutin Or Rifampin And A Single Dose Of TMC207 In Healthy Subjects

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Pharmacokinetic profiles determined for rifabutin, desacetyl rifabutin, rifampin, and desacetyl rifampin: Cmin [ Time Frame: Pre-dose and 2 hrs post dose in Period 2 on Days 27-30, 35 & 41. ] [ Designated as safety issue: No ]
  • Pharmacokinetic profiles over 336 hours, determined for TMC207 and M2 after administration of TMC207 alone and in combination with steady-state rifabutin or rifampin: Cmax, AUC(0-t), Tmax, T1/2, Kel, ratios Cmaxtest/Cmaxref, AUC(0-t,test)/AUC(0-t,ref) [ Time Frame: Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, and 336 hours after TMC207 dosing in both Period 1 (Study Day 1, Groups 1 and 2) and 2 (Study Day 29, Groups 1 and 2). ] [ Designated as safety issue: No ]
  • Safety and tolerability of TMC207 by assessment of solicited and unsolicited adverse events, including symptoms, physical findings, lab testing, ophthalmologic exams & Electrocardiogram (ECG) changes [ Time Frame: Over 60 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Cell-associated levels of TMC207 and its M2 metabolite in peripheral blood mononuclear cells (PBMCs) after single and multiple doses. [ Time Frame: 0, 1, 4, 8, 12, 72, 120, 168, 240, and 336 hours after TMC207 dosing. ] [ Designated as safety issue: No ]

Enrollment: 33
Study Start Date: October 2011
Study Completion Date: May 2012
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1
16 subjects: TMC207 400mg orally on days 1 and 29, rifabutin 300mg orally, every day on day 20-41
Drug: Rifabutin
Rifabutin 300 mg orally on days 20-41
Drug: TMC207
TMC207 400 mg orally on days 1 and 29
Experimental: Group 2
16 subjects: TMC207 400mg orally on days 1 and 29, rifampin 600mg orally, every day on day 20-41
Drug: Rifampin
Rifampin 600 mg orally on days 20-41
Drug: TMC207
TMC207 400 mg orally on days 1 and 29

Detailed Description:

32 (16 per treatment group) healthy male or female subjects, 18 - 45 years old will be enrolled.Subjects will receive two single oral doses of 400mg TMC207, first on Study Day 1 followed by a 28-day wash-out, the second on Study Day 29. On Study Day 28, any abnormal safety labs will be reviewed by study physician and be determined not to meet the exclusion criteria before administration of the second dose of TMC207. Rifabutin 300mg (Group 1) or rifampin 600mg (Group 2) will be administered once daily during Period 2 from Study Day 20 through Study Day 41. The primary endpoint for the study (pharmacokinetics, safety and tolerability of TMC207 (and its M2 metabolite) will be determined on the final study visit, Day 57 (28 days after the last TMC207 dose in Period 2).

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Aged between 18 and 45 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 <35.0 kg/m^2
  • 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, ophthalmologic exam, the results of blood biochemistry, and hematology tests, and a urinalysis carried out at screening (See Section 7.2).
  • Subjects will be enrolled in this study only if they have undergone vasectomy/complete hysterectomy, tubal ligation, or other sterilizing procedure, or the subject is a post-menopausal woman for more than two years, or if sexually active subjects agree to use two of the following forms of adequate contraception during the study and for 12 weeks after the final dose: abstinence, condoms with or without spermicide gel, diaphragm with spermicide gel, hormonal or non-hormonal intrauterine device, oral contraceptive pills, and depot progesterone injections. If a subject is usually not sexually active but becomes active, the subject and his or her partner must use two of the listed contraceptive methods.

Exclusion Criteria:

Medical History

  • 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 Principal Investigator) history of acute illness (resolved within 4 weeks of screening), asthma, 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., rifabutin, rifampin, and TMC207).
  • Subjects with QTcB [Bazett correction] interval > 450ms at screening
  • Subjects with any other clinically significant Electrocardiogram (ECG) abnormality at screening, such as arrhythmia, ischemia, or evidence of heart failure or with a family history of Long QT Syndrome.
  • History or evidence of ophthalmologic diseases except for routine corrected hyperopia, myopia, and presbyopia.
  • Recent history (within past 30 days) of vertigo/nausea.

Specific Treatments

  • Current use of any azole antifungal agent
  • Use of concomitant medication, including over-the-counter products and dietary supplements, without approval from study staff. Subjects will be treated based on symptom presentation, with the exception of medications that affect p450 and 3a metabolic pathways (refer to the MOP for a list of acceptable medications). During outpatient time periods, subjects will be required to discuss with the study staff and receive approval before self-administering any medication. After gaining approval, subjects will also be asked to record any medication taken during outpatient time periods in a provided log.
  • Participation in an investigational drug trial within 60 days prior to the first intake of trial medication and during the duration of the study.
  • 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.

Based on Laboratory Abnormalities

  • Positive HIV-1 or HIV-2 test by Enzyme-linked immunosorbent assay (ELISA) 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 amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids; along with serum alcohol level.
  • Subjects with the following laboratory abnormalities at screening as defined by the National Institute of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (Appendix C) and in accordance with the normal ranges of the clinical laboratory:

    1. Serum creatinine grade 1 or greater [> 1.0 x Upper limit of lab normal range (ULN)],
    2. Pancreatic lipase grade 1 or greater (> 1.0 x ULN),
    3. Hemoglobin grade 1 or greater (</= 10.5 g/dL),
    4. Platelet count grade 1 or greater (</= 99000/mm^3),
    5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater (> 1.0 x ULN),
    6. Total bilirubin grade 1 or greater (> 1.0 x ULN),
    7. Creatine kinase grade 1 or greater (>1.0 x ULN),
    8. Troponin grade 1 or greater (1.0 x UNL), or
    9. Any other toxicity grade 2 or above, including: proteinuria (spot urine) > 1+ and gross hematuria. For the second dose of TMC207, any other toxicity grade 3 or above, including: proteinuria (spot urine) > 1+ and gross hematuria
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01341184

Locations
United States, Ohio
Case Western Reserve University - Case Medical Center - Infectious Disease & HIV Medicine
Cleveland, Ohio, United States, 44106-1716
Sponsors and Collaborators
  More Information

No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01341184     History of Changes
Other Study ID Numbers: 10-0043, N01AI80026C
Study First Received: April 7, 2011
Last Updated: April 25, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
tuberculosis, rifabutin, rifampin, TMC207

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Rifampin
Rifabutin
Bedaquiline
Antibiotics, Antitubercular
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antitubercular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 31, 2014