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

NCT01571414 | Completed Phase 1 DMC

• 3 other identifiers: A530611829ACTG5306
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 4

Brief 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.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (9)

• 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 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 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 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 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 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 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 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 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 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 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 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 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 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 through participants' last study visit at Days 29 to 36

Study Arms (5)

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.

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.

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.

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.

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.

Drug: PA-824; Drug: Rifampin (RIF)

Interventions

PA-824 DRUG

200-mg tablets once a day

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) DRUG

600-mg tablets once a day

Arm 1A-EFV and PA-824; Arm 1B-EFV and PA-824

Lopinavir/Ritonavir (LPV/r) DRUG

400-mg/100-mg tablets twice a day

Arm 2A-LPV/r and PA-824; Arm 2B-LPV/r and PA-824

Rifampin (RIF) DRUG

300-mg capsules once a day

Arm 3-RIF and PA-824

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (4)

Ucsf Hiv/Aids Crs

San Francisco, California, 94110, United States

Location

Johns Hopkins University CRS

Baltimore, Maryland, 21205, United States

Location

Ohio State University CRS

Columbus, Ohio, 43210, United States

Location

Vanderbilt Therapeutics (VT) CRS

Nashville, Tennessee, 37204, United States

Location

Related Publications (3)

• 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.

  PMID: 15917524 BACKGROUND

• 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.

  PMID: 19039139 BACKGROUND

• 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.

  PMID: 24957823 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

pretomanid; efavirenz; Lopinavir; Rifampin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Kelly E. Dooley, MD, PhD

  Johns Hopkins University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2012
• First Posted: April 5, 2012
• Study Start: May 1, 2012
• Primary Completion: May 1, 2013
• Study Completion: May 1, 2013
• Last Updated: November 5, 2021

Record last verified: 2015-04

Locations

US (4)