TuberculosisPhase 1NCT01571414

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

A Phase 1 study testing PA-824, Efavirenz (EFV) and Lopinavir/Ritonavir (LPV/r) in people with Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 yearsHealthy volunteers can take part
Conditions the study is for: Tuberculosis
What is being tested?: PA-824, Efavirenz (EFV) and Lopinavir/Ritonavir (LPV/r)
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 52 participants
Where: 4 sitesUnited States
Study dates: May 2012to May 2013
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

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

Show all 14Show fewer

Platelet count greater than or equal to 125,000/cu mm
Absolute neutrophil count greater than or equal to 1,250/cu mm
Serum albumin greater than or equal to the lower limit of normal for the laboratory
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
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

Who cannot join

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

Show all 16Show fewer

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

Trial locations and contacts

4 sites in 1 country.

United States4 sites

Johns Hopkins University CRS
Baltimore, Maryland, 21205
Ohio State University CRS
Columbus, Ohio, 43210
Vanderbilt Therapeutics (VT) CRS
Nashville, Tennessee, 37204
Ucsf Hiv/Aids Crs
San Francisco, California, 94110

Other trials in United States

About this study

Official title: A Phase I, Three-Arm Safety, Tolerability, and Pharmacokinetic Interaction Study of PA-824, an Investigational Nitroimidazole for the Treatment of Tuberculosis, Together With Efavirenz, Ritonavir-Boosted Lopinavir, or Rifampin

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.

Read the detailed description

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.

Conditions: Tuberculosis
Being tested: PA-824, Efavirenz (EFV), Lopinavir/Ritonavir (LPV/r), Rifampin (RIF)
Medical subject headings: Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

PA-824Drug
200-mg tablets once a day
Efavirenz (EFV)Drug
600-mg tablets once a day
Lopinavir/Ritonavir (LPV/r)Drug
400-mg/100-mg tablets twice a day
Rifampin (RIF)Drug
300-mg capsules once a day

Study groups in NCT01571414
Study group	Role	What they receive
Arm 1A-EFV and PA-824	Experimental	Participants will receive PA-824 on Days 1 to 7, no study medication on Days 8 to 21, EFV on Days 22 to 35, and EFV plus PA-824 on Days 36 to 42. Inpatient study visits will occur at Days 7, 34, and 41 to 42. Receives: Drug: PA-824; Drug: Efavirenz (EFV)
Arm 1B-EFV and PA-824	Experimental	Participants will receive EFV on Days 1 to 14, EFV plus PA-824 on Days 15 to 21, no study medication on Days 22 to 35, and PA-824 on Days 36 to 42. Inpatient study visits will occur at Days 13, 20 to 21, and 42. Receives: Drug: PA-824; Drug: Efavirenz (EFV)
Arm 2A-LPV/r and PA-824	Experimental	Participants will receive PA-824 on Days 1 to 7, no study medication on Days 8 to 21, LPV/r on Days 22 to 35, and LPV/r plus PA-824 on Days 36 to 42. Inpatient study visits will occur at Days 7, 35, and 42. Receives: Drug: PA-824; Drug: Lopinavir/Ritonavir (LPV/r)
Arm 2B-LPV/r and PA-824	Experimental	Participants will receive LPV/r on Days 1 to 14, LPV/r plus PA-824 on Days 15 to 21, no study medication on Days 22 to 35, and PA-824 on Days 36 to 42. Inpatient study visits will occur at Days 14, 21, and 42. Receives: Drug: PA-824; Drug: Lopinavir/Ritonavir (LPV/r)
Arm 3-RIF and PA-824	Experimental	Participants will receive PA-824 on Days 1 to 7, RIF on Days 8 to 14, and RIF plus PA-824 on Days 15 to 21. Inpatient study visits will occur at Days 7 and 21. Receives: Drug: PA-824; Drug: Rifampin (RIF)

What is being measured

The primary outcome is the main question the study is designed to answer.

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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Measured at participants' inpatient study visits at Days 7 and 21

Secondary outcomes (19)

Arm 1: PA-824 PK parameters Cmin when dosed alone and when dosed together with EFV 600 mg daily
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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 Cmin when EFV is dosed alone and when dosed together with PA-824 200 mg daily
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Measured at participants' inpatient study visits at Days 7 and 21

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

May 2012May 2013

First posted5 Apr 2012 (estimated)
Study startMay 2012
Primary completionMay 2013
Study completionMay 2013

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (3)Papers the sponsor has linked to this study.
Other trials for TuberculosisStudies of the same condition, open and under way.
More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Enrolment: 52 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01571414
Sponsor's protocol ID: A5306
Other IDs: 11829, ACTG5306
Status last verified: Apr 2015
First submitted: 20 Mar 2012
Last updated: 5 Nov 2021
Results posted: No
Data monitoring committee: Yes

Publications

Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, Reynolds RC, Orme IM. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 2005 Jun;49(6):2294-301. doi: 10.1128/AAC.49.6.2294-2301.2005.
PubMed 15917524
Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, Dowd CS, Lee IY, Kim P, Zhang L, Kang S, Keller TH, Jiricek J, Barry CE 3rd. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008 Nov 28;322(5906):1392-5. doi: 10.1126/science.1164571.
PubMed 19039139
Dooley KE, Luetkemeyer AF, Park JG, Allen R, Cramer Y, Murray S, Sutherland D, Aweeka F, Koletar SL, Marzan F, Bao J, Savic R, Haas DW; AIDS Clinical Trials Group A5306 Study Team. Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. Antimicrob Agents Chemother. 2014 Sep;58(9):5245-52. doi: 10.1128/AAC.03332-14. Epub 2014 Jun 23.
PubMed 24957823

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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All Tuberculosis trials

Study at a glance

From the registry record, last updated by the sponsor on 5 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase I, Three-Arm Safety, Tolerability, and Pharmacokinetic Interaction Study of PA-824, an Investigational Nitroimidazole for the Treatment of Tuberculosis, Together With Efavirenz, Ritonavir-Boosted Lopinavir, or Rifampin
ClinicalTrials.gov ID: NCT01571414
Acronym / sponsor ID: A5306
Conditions: Tuberculosis
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 52 participants (actual)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
Study start: May 2012
Primary completion: May 2013 (actual)
Study completion: May 2013 (actual)
First posted: 5 Apr 2012 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Number of arms: 5

Arm	Type	Receives
Arm 1A-EFV and PA-824	Experimental	Drug: PA-824, Drug: Efavirenz (EFV)Participants will receive PA-824 on Days 1 to 7, no study medication on Days 8 to 21, EFV on Days 22 to 35, and EFV plus PA-824 on Days 36 to 42. Inpatient study visits will occur at Days 7, 34, and 41 to 42.
Arm 1B-EFV and PA-824	Experimental	Drug: PA-824, Drug: Efavirenz (EFV)Participants will receive EFV on Days 1 to 14, EFV plus PA-824 on Days 15 to 21, no study medication on Days 22 to 35, and PA-824 on Days 36 to 42. Inpatient study visits will occur at Days 13, 20 to 21, and 42.
Arm 2A-LPV/r and PA-824	Experimental	Drug: PA-824, Drug: Lopinavir/Ritonavir (LPV/r)Participants will receive PA-824 on Days 1 to 7, no study medication on Days 8 to 21, LPV/r on Days 22 to 35, and LPV/r plus PA-824 on Days 36 to 42. Inpatient study visits will occur at Days 7, 35, and 42.
Arm 2B-LPV/r and PA-824	Experimental	Drug: PA-824, Drug: Lopinavir/Ritonavir (LPV/r)Participants will receive LPV/r on Days 1 to 14, LPV/r plus PA-824 on Days 15 to 21, no study medication on Days 22 to 35, and PA-824 on Days 36 to 42. Inpatient study visits will occur at Days 14, 21, and 42.
Arm 3-RIF and PA-824	Experimental	Drug: PA-824, Drug: Rifampin (RIF)Participants will receive PA-824 on Days 1 to 7, RIF on Days 8 to 14, and RIF plus PA-824 on Days 15 to 21. Inpatient study visits will occur at Days 7 and 21.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (14 listed)

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:

Key exclusion criteria (16 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
PA-824200-mg tablets once a day	Drug	Arm 1A-EFV and PA-824, Arm 1B-EFV and PA-824, Arm 2A-LPV/r and PA-824, Arm 2B-LPV/r and PA-824, Arm 3-RIF and PA-824
Efavirenz (EFV)600-mg tablets once a day	Drug	Arm 1A-EFV and PA-824, Arm 1B-EFV and PA-824
Lopinavir/Ritonavir (LPV/r)400-mg/100-mg tablets twice a day	Drug	Arm 2A-LPV/r and PA-824, Arm 2B-LPV/r and PA-824
Rifampin (RIF)300-mg capsules once a day	Drug	Arm 3-RIF and PA-824

Primary outcome

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

19 secondary outcomes

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)
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

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 5 Nov 2021.
Background: PubMed 15917524Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, Reynolds RC, Orme IM. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 2005 Jun;49(6):2294-301. doi: 10.1128/AAC.49.6.2294-2301.2005.
Background: PubMed 19039139Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, Dowd CS, Lee IY, Kim P, Zhang L, Kang S, Keller TH, Jiricek J, Barry CE 3rd. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008 Nov 28;322(5906):1392-5. doi: 10.1126/science.1164571.
Derived from this study: PubMed 24957823Dooley KE, Luetkemeyer AF, Park JG, Allen R, Cramer Y, Murray S, Sutherland D, Aweeka F, Koletar SL, Marzan F, Bao J, Savic R, Haas DW; AIDS Clinical Trials Group A5306 Study Team. Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. Antimicrob Agents Chemother. 2014 Sep;58(9):5245-52. doi: 10.1128/AAC.03332-14. Epub 2014 Jun 23.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Kelly E. Dooley, MD, PhD study chair

Johns Hopkins University

4 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01571414, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2021.