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

TB is a global public health threat. In 2009, there were an estimated 9.4 million cases of
TB and 1.8 million deaths from the disease. TB treatment regimens are often lengthy and
complex, and multidrug-resistant (MDR) TB is emerging as a worldwide epidemic. TB is also
one of the most common causes of death among people infected with HIV. PA-824 is an
experimental drug developed for the treatment of TB. This study will evaluate the safety,
tolerability, and pharmacokinetic (PK) drug interactions between PA-824 and EFV, LPV/r, or
RIF.

This study will enroll healthy adults who are not infected with HIV or TB. Participants will
be enrolled into one of three arms, with Arms 1 and 2 each consisting of two groups.
Participants in Arm 1 will be randomly assigned to receive PA-824 alone or EFV alone
followed by EFV plus PA-824 in one of two sequences. Participants in Arm 2 will be randomly
assigned to receive PA-824 alone or LPV/r alone followed by LPV/r plus PA-824 in one of two
sequences. For participants in Arms 1 and 2, there will be a 14-day washout period between
treatments, where participants will not receive any medication. Participants in Arm 3 will
receive PA-824 alone, followed by RIF alone, and then RIF plus PA-824. Participants in Arms
1 and 2 will attend outpatient study visits at study entry and either Days 3, 22, and 29 or
Days 7, 36, and 39, depending on which group they are in. Participants in Arm 3 will attend
outpatient study visits at study entry and Days 3, 10, and 15. At most study visits,
participants will undergo a physical examination, vital sign measurements, medication and
medical history review, and blood collection. Participants will complete a medication and
symptom diary throughout the study.

All participants also will be admitted to an inpatient clinical research unit two or three
times during the study, depending on which arm they are enrolled in. Each inpatient visit
will last 1 or 2 days. During the inpatient visits, participants will undergo several blood
collections throughout the day; select visits also will include an electrocardiogram (ECG).

Participants in Arms 1 and 2 will receive the last dose of their assigned medication on Day
42. Participants in Arm 3 will receive the last dose of their assigned medication on Day 21.
A final study visit will occur for all participants 1 to 2 weeks later.

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