Rifapentine Plus Moxifloxacin for Treatment of Pulmonary Tuberculosis

Tuberculosis Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00728507
• Other study ID #: 06-0018
• Status: Active, not recruiting
• Phase: Phase 2
• First received: July 30, 2008
• Last updated: April 1, 2013
• Start date: November 2009
• Est. completion date: December 2013

Study information

• Verified date: April 2013
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBrazil: National Committee of Ethics in ResearchBrazil: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 216
• Est. completion date: December 2013
• Est. primary completion date: August 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

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.
• Isoniazid, Rifampin, Pyrazinamide, Ethambutol
Administered per standard of care for TB treatment

Locations

Country	Name	City	State
Brazil	Centro de Referência Professor Hélio Fraga - ENSP - FIOCRUZ	Curicica	Rio de Janeiro
Brazil	Hospital Universitario Clementio Fraga Filho	Rio de Janeiro
Brazil	Posto de Saude Albert Sabin	Rio de Janeiro	RJ

Sponsors (4)

Lead Sponsor	Collaborator
Johns Hopkins University	Helio Fraga Reference Center, Fiocruz, Municipal Health Secretary of Rio de Janeiro, Universidade Federal do Rio de Janeiro

Country where clinical trial is conducted

Brazil, 

References & Publications (3)

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. Epub 2003 Oct 24. — View 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. Epub 2004 Aug 11. — View 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. Epub 2006 Mar 30. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To compare, by treatment group, the proportions of patients with a negative sputum culture at the end of intensive phase therapy.		Week 8	No
Primary	To compare the safety and tolerability of the 2 intensive phase regimens.		Weekly or more frequent	Yes
Secondary	To compare the time to respiratory culture conversion of the 2 intensive phase regimens, using data from weekly cultures.		Weekly	No
Secondary	To compare, by treatment group, the proportions of subjects who experience treatment failure.		Month 6	No
Secondary	To compare, by HIV serostatus, a) the safety of the 2 intensive phase regimens, b) the proportions of patients with negative sputum cultures at the end of intensive phase therapy, and c) the time to culture conversion using data from weekly cultures.		Weekly or more frequent	Yes
Secondary	To compare, in subjects with versus without cavitation on baseline chest x-ray, the proportions of patients with negative sputum cultures at the end of intensive phase therapy.		Week 8	No
Secondary	To store serum for future assessment of hypersensitivity to study drugs, should it occur; to store plasma for future assessment of drug concentrations		Future	Yes