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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
52
200-mg tablets once a day
600-mg tablets once a day
400-mg/100-mg tablets twice a day
300-mg capsules once a day
Ucsf Hiv/Aids Crs
San Francisco, California, United States
Johns Hopkins University CRS
Baltimore, Maryland, United States
Ohio State University CRS
Columbus, Ohio, United States
Vanderbilt Therapeutics (VT) CRS
Nashville, Tennessee, United States
Arm 1: PA-824 PK parameters area under the concentration-time curve (AUC) of 24 hours when dosed alone and when dosed together with EFV 600 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 1: Grade 2 or higher signs and symptoms observed while on study and during the follow-up
Time frame: Measured through participants' last study visit at Days 49 to 56
Arm 2: PA-824 PK parameters AUC of 24 hours when dosed alone and when dosed together with LPV/r 400/100 mg twice daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 2: Grade 2 or higher signs and symptoms observed while on study and during the follow-up
Time frame: Measured through participants' last study visit at Days 49 to 56
Arm 3: PA-824 PK parameters AUC of 24 hours when dosed alone and when dosed together with RIF 600 mg once daily
Time frame: Measured at participants' inpatient study visits at Days 7 and 21
Arm 3: Grade 2 or higher signs and symptoms observed while on study and during the follow-up
Time frame: Measured through participants' last study visit at Days 29 to 36
Arm 1: PA-824 PK parameters Cmax when dosed alone and when dosed together with EFV 600 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 2: PA-824 PK parameters Cmax when dosed alone and when dosed together with LPV/r 400/100 mg twice daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 3: PA-824 PK parameters Cmax when dosed alone and when dosed together with RIF 600 mg once daily
Time frame: Measured at participants' inpatient study visits at Days 7 and 21
Arm 1: PA-824 PK parameters Cmin when dosed alone and when dosed together with EFV 600 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 1: EFV PK parameters AUC of 24 hours when EFV is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 2: PA-824 PK parameters Cmin when dosed alone and when dosed together with LPV/r 400/100 mg twice daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 2: LPV PK parameters AUC of 12 hours when LPV/r is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 3: PA-824 PK parameters Cmin when dosed alone and when dosed together with RIF 600 mg daily
Time frame: Measured through participants' last study visit at Days 29 to 36
Arm 1: PA-824 PK parameters T1/2 when dosed alone and when dosed together with EFV 600 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 1: PA-824 PK parameters CL/F when dosed alone and when dosed together with EFV 600 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 1: EFV PK parameters Cmax when EFV is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
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Arm 1: EFV PK parameters Cmin when EFV is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 1: EFV PK parameters CL/F when EFV is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 1: EFV PK parameters T1/2 when EFV is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 34, and 41 to 42 (Arm 1A) and at Days 13, 20 to 21, and 42 (Arm 1B)
Arm 2: PA-824 PK parameters T1/2 when dosed alone and when dosed together with LPV/r 400/100 mg twice daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 2: PA-824 PK parameters CL/F when dosed alone and when dosed together with LPV/r 400/100 mg twice daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 2: LPV PK parameters Cmax when LPV/r is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 2: LPV PK parameters Cmin when LPV/r is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 2: LPV PK parameters CL/F when LPV/r is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 2: LPV PK parameters T1/2 when LPV/r is dosed alone and when dosed together with PA-824 200 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7, 35, and 42 (Arm 2A) and at Days 14, 21, and 42 (Arm 2B)
Arm 3: PA-824 PK parameters T1/2 when dosed alone and when dosed together with RIF 600 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7 and 21
Arm 3: PA-824 PK parameters CL/F when dosed alone and when dosed together with RIF 600 mg daily
Time frame: Measured at participants' inpatient study visits at Days 7 and 21