Rifapentine Plus Moxifloxacin for Treatment of Pulmonary Tuberculosis

A Phase II Randomized, Open-label Trial of a Rifapentine Plus Moxifloxacin-Based Regimen for Intensive Phase Treatment of Smear-Positive Pulmonary Tuberculosis

Although effective therapy for tuberculosis is available, TB continues to cause significant problems worldwide, and rates of multi-drug resistant (MDR) TB cases are on the rise. A major obstacle to the control of TB is poor adherence with lengthy (usually 6 months) and complicated treatment regimens. Incomplete TB treatment can lead to serious consequences such as increased severity of illness and death, prolonged infectiousness and transmission in the community, and the development of drug resistance. The development of new treatment strategies with more stronger drugs could lead to shorter and simpler regimens. A TB treatment regimen that allowed treatment duration to be meaningfully decreased would have important public health implications.

This trial will compare the effect and safety of a new oral regimen to that of the standard regimen for the first phase of treatment for pulmonary tuberculosis.

The experimental regimen will consist of the following:

• Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid.

The standard control intensive phase regimen will consist of the following:

• Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid.

Following intensive phase therapy (the study phase), all patients will be treated with a non-experimental continuation phase regimen.

In mice, the combination of Moxifloxacin and Rifapentine have cured the animals significantly faster than the standard regimen and this study will be the first step to see if the potential is also there in humans.

Study Overview

• Status: Terminated
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: Rifapentine, Moxifloxacin, Pyrazinamide, Isoniazid; Drug: Isoniazid, Rifampin, Pyrazinamide, Ethambutol

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil
    • Hospital Universitario Clementio Fraga Filho
  • RJ
    • Rio de Janeiro, RJ, Brazil, 20211-110
      • Posto de Saude Albert Sabin
  • Rio de Janeiro
    • Curicica, Rio de Janeiro, Brazil, 22.780-192
      • Centro de Referência Professor Hélio Fraga - ENSP - FIOCRUZ

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Presumptive diagnosis of sputum smear-positive pulmonary TB.
• Age: ≥18 years
• Seven (7) or fewer days of multidrug therapy for TB disease in the preceding 6 months.
• Seven (7) or fewer days of fluoroquinolone therapy in the preceding 3 months.
• Documentation of HIV infection status.
• For HIV seropositive individuals, a CD4 T lymphocyte count of greater than or equal to 200 cells/mm3.

• Documentation of study baseline laboratory parameters done at, or ≤ 14 days prior to screening:

  • AST less than or equal to 2.5 times upper limit of normal.
  • Total bilirubin level less than 2.5 times upper limit of normal.
  • Creatinine level less than 2 times upper limit of normal.
  • Hemoglobin level of at least 8.0 g/dl.
  • Platelet count of at least 75,000 mm3.
  • Potassium level of at least 3.5.
  • Negative pregnancy test (women of childbearing potential).
• Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs).
• Male or nonpregnant, nonnursing female.
• Provision of informed consent.

Exclusion Criteria:

• CD4 count < 200 cells/cu mm.
• Presence of active AIDS-related opportunistic infection (other than TB) or active AIDS-related malignancy.
• Known intolerance to any of the study drugs.
• Concomitant disorders or conditions for which any of the study drugs is contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis.
• Inability to take oral medication.
• Central nervous system TB.
• Pulmonary silicosis.
• Current or planned therapy, during study phase (intensive phase of TB treatment), with any one or more of the following drugs: quinidine, procainamide, amiodarone, sotalol, disopyramide, terfenadine, cisapride, erythromycin, clarithromycin, phenothiazines, haloperidol, olanzapine, ziprasidone, tricyclic antidepressants, chronic corticosteroids administered either orally or intravenously, chronic fluconazole,chronic itraconazole, chronic ketoconazole, oral or intravenous tacrolimus, oral or intravenous cyclosporine, HIV protease inhibitor, HIV non-nucleoside reverse transcriptase inhibitor.
• Concurrent severe and/or uncontrolled medical or psychiatric condition that, in the opinion of the investigator, could cause unacceptable safety risks or compromise compliance with the protocol.
• Unable or unwilling to receive directly observed therapy and/or adhere with follow-up (e.g. due to residence remote from the study site).
• Refusal of consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid.	Drug: Rifapentine, Moxifloxacin, Pyrazinamide, Isoniazid; Rifapentine:150mg tablets, dose = 300mg for subjects <= 45kg and 450mg for those >45kg by mouth once a day for 8 weeks; Moxifloxacin 400mg tablet by mouth once a day for 8 weeks, Isoniazid and Pyrazinamide per standard of care for TB treatment.; Other Names: Priftin, Avelox
Active Comparator: 2; Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid.	Drug: Isoniazid, Rifampin, Pyrazinamide, Ethambutol; Administered per standard of care for TB treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Compare, by Treatment Group, the Percentage of Patients With a Negative Sputum Culture at the End of Intensive Phase Therapy.	LJ culture conversion	Week 8
To Compare the Safety and Tolerability of the 2 Intensive Phase Regimens.	Study was prematurely terminated and data was not collected for this outcome measure.	Weekly or more frequent

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: Universidade Federal do Rio de Janeiro
• Investigators: Principal Investigator: Susan Dorman, MD, Johns Hopkins University

Publications and helpful links

General Publications

• Rosenthal IM, Williams K, Tyagi S, Peloquin CA, Vernon AA, Bishai WR, Grosset JH, Nuermberger EL. Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. Am J Respir Crit Care Med. 2006 Jul 1;174(1):94-101. doi: 10.1164/rccm.200602-280OC. Epub 2006 Mar 30.
• Nuermberger EL, Yoshimatsu T, Tyagi S, O'Brien RJ, Vernon AN, Chaisson RE, Bishai WR, Grosset JH. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med. 2004 Feb 1;169(3):421-6. doi: 10.1164/rccm.200310-1380OC. Epub 2003 Oct 24.
• Nuermberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I, O'Brien RJ, Vernon AA, Chaisson RE, Bishai WR, Grosset JH. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. Am J Respir Crit Care Med. 2004 Nov 15;170(10):1131-4. doi: 10.1164/rccm.200407-885OC. Epub 2004 Aug 11.
• Conde MB, Mello FC, Duarte RS, Cavalcante SC, Rolla V, Dalcolmo M, Loredo C, Durovni B, Armstrong DT, Efron A, Barnes GL, Marzinke MA, Savic RM, Dooley KE, Cohn S, Moulton LH, Chaisson RE, Dorman SE. A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis. PLoS One. 2016 May 9;11(5):e0154778. doi: 10.1371/journal.pone.0154778. eCollection 2016.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: July 30, 2008
• First Submitted That Met QC Criteria: July 31, 2008
• First Posted (Estimate): August 5, 2008

Study Record Updates

• Last Update Posted (Actual): April 20, 2017
• Last Update Submitted That Met QC Criteria: March 8, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Tuberculosis; Moxifloxacin; Rifapentine
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Moxifloxacin; Rifapentine; Rifampin; Isoniazid; Pyrazinamide; Ethambutol
• Other Study ID Numbers: 06-0018