Evaluating the Safety and Drug Interaction of PA-824, an Investigational Tuberculosis Medication, Together With Efavirenz, Ritonavir-Boosted Lopinavir, or Rifampin

• Status: Completed
• Trial end date: 2013-05-01
• Target enrollment: 0
• Participant gender: All

Summary

Tuberculosis (TB) is a global public health concern and developing new treatment regimens is an important research priority. PA-824 is an experimental TB medication. This study will evaluate the safety and tolerability of PA-824 when combined with efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r), which are medications used to treat HIV infection, or rifampin (RIF), which is a medication used to treat TB. Study researchers will examine the safety and tolerability of these drug combinations and how the medications affect the levels of PA-824 in the blood.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Efavirenz; Lopinavir; Rifampin; Ritonavir

Criteria

Inclusion Criteria:

• Contraception requirements: Females of reproductive potential must have a negative serum or urine beta-human choriogonadotropin (β-HCG) pregnancy test performed within 48 hours before study entry. All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). If participating in sexual activity that could lead to pregnancy, participants must agree to use two reliable forms of contraceptives simultaneously while on study and for a number of weeks after the final study visit as defined in the protocol. More information on this criterion can be found in the protocol.

• Able and willing to provide written informed consent

• Absence of HIV-1 infection, as documented by any licensed enzyme-linked immunosorbent assay (ELISA) test kit, within 21 days prior to study entry

• Creatinine clearance of greater than 50 mL/min, within 21 days prior to study entry, calculated by the Cockcroft-Gault method. More information on this criterion can be found in the protocol.

• Laboratory values obtained within 21 days prior to study entry:

1. Hemoglobin greater than 12 g/dL for men and greater than 11 g/dL for women

2. Platelet count greater than or equal to 125,000/cu mm

3. Absolute neutrophil count greater than or equal to 1,250/cu mm

4. Serum albumin greater than or equal to the lower limit of normal for the laboratory

5. Serum potassium greater than or equal to the lower limit of normal and less than or equal to the upper limit of normal for the laboratory

6. Serum alanine aminotransferase (ALT) less than or equal to the upper limit of normal (ULN) for the laboratory

• Note: Screening laboratory evaluations may be repeated if one or more of the values are out of range. It is preferable, although not required, for prospective participants to fast (i.e., nothing by mouth [NPO] except water) for 4 hours prior to drawing samples for screening serum albumin, serum potassium, and serum ALT evaluations.

• Hepatitis B surface antigen negative, performed by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory within 21 days prior to study entry

• Hepatitis C virus (HCV) antibody negative or, if the participant is known to have a positive hepatitis C antibody test, negative HCV RNA test, performed by a CLIA-certified laboratory within 21 days prior to study entry

Exclusion Criteria:

• Use of any prescription or nonprescription medication known to inhibit or induce CYP3A or CYP2B6 metabolizing enzymes (refer to the manufacturers' package inserts for individual drugs) within 30 days prior to study entry

• Planned use during the study, from study entry through the last PK blood draw, of any of the following: prescription medication(s) [excluding IUDs that elute locally active hormonal contraceptives], herbal supplement(s), nutritional supplement(s), or over-the-counter medication(s). Note: Multivitamins, acetaminophen (up to 650 mg every 6 hours as an analgesic), ibuprofen (up to 600 mg twice daily), naproxen (up to 500 mg twice daily for pain or headache), and diphenhydramine (up to 25 mg daily for insomnia or seasonal allergies) are permitted.

• Hospitalization for any reason within 14 days prior to study entry

• Pharmacotherapy for serious illness within 14 days prior to study entry

• Use of any prescription medication(s) within 14 days prior to study entry

• Receipt of any investigational study drug, vaccine, or treatment within 21 days prior to study entry

• Known allergy/sensitivity or any hypersensitivity to PA-824, EFV, LPV, RTV, RIF, or components of their formulations

• As determined by the site investigator, a significant previous or active history of cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, or immunologic disease(s); this is inclusive of chronic illnesses or gastrointestinal conditions that may affect drug absorption, etc.

• Any medical condition that, in the opinion of the site investigator, would interfere with the participant's ability to participate in the study

• Active illicit drug use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements

• Clinical evidence of active TB. Note: Clinical evidence of active TB is based on history and physical examination. No other screening tests for TB are required for the study.

• Inability to abstain from consuming alcoholic beverages during defined periods throughout the study and grapefruits, mandarin oranges, and grapefruit juice for the entire duration of the study. Note: Participants are permitted to consume alcoholic beverages only during the washout period of Arms 1 and 2. Participants must agree to abstain from consuming alcoholic beverages for the duration of Arm 3.

• For smokers, inability to smoke less than or equal to 5 cigarettes per day for the entire duration of the study

• Breastfeeding

• ECG showing first-degree or greater heart block or QTc greater than 450 ms within 21 days prior to study entry. More information on this criterion can be found in the protocol.

• Frequent or severe headaches, defined as more than two headaches per week on average during the last 30 to 60 days prior to study entry or headaches greater than or equal to once every 30 days during the last 90 days prior to study entry that were severe enough to interfere with activities of daily living or ability to work or carry out daily responsibilities