Clinical trial NCT00728507: Rifapentine Plus Moxifloxacin for Treatment of Pulmonary Tuberculosis
Official title: A Phase II Randomized, Open-label Trial of a Rifapentine Plus Moxifloxacin-Based Regimen for Intensive Phase Treatment of Smear-Positive Pulmonary Tuberculosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: Tuberculosis
Moxifloxacin
Rifapentine
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Universidade Federal do Rio de Janeiro
First posted: 2008-08-05
Enrollment: 121
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: To Compare, by Treatment Group, the Percentage of Patients With a Negative Sputum Culture at the End of Intensive Phase Therapy.
timeFrame: Week 8
measure: To Compare the Safety and Tolerability of the 2 Intensive Phase Regimens.
timeFrame: Weekly or more frequent
Secondary outcomes:
Other outcomes:
Locations:
city: Curicica
country: Brazil
facility: Centro de Referência Professor Hélio Fraga - ENSP - FIOCRUZ
state: Rio de Janeiro
city: Rio de Janeiro
country: Brazil
facility: Posto de Saude Albert Sabin
state: RJ
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitario Clementio Fraga Filho
Study officials:
affiliation: Johns Hopkins University
name: Susan Dorman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.