Rifapentine Plus Moxifloxacin for Treatment of Pulmonary Tuberculosis

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00728507
• Collaborator: Universidade Federal do Rio de Janeiro (Other)
• Enrollment: 121
• Locations: 3
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 40.3
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Rifapentine, Moxifloxacin, Pyrazinamide, Isoniazid; Drug: Isoniazid, Rifampin, Pyrazinamide, Ethambutol	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Nov 1, 2009
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. To Compare, by Treatment Group, the Percentage of Patients With a Negative Sputum Culture at the End of Intensive Phase Therapy. [Week 8]

   LJ culture conversion

2. To Compare the Safety and Tolerability of the 2 Intensive Phase Regimens. [Weekly or more frequent]

   Study was prematurely terminated and data was not collected for this outcome measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centro de Referência Professor Hélio Fraga - ENSP - FIOCRUZ	Curicica	Rio de Janeiro	Brazil	22.780-192
2	Posto de Saude Albert Sabin	Rio de Janeiro	RJ	Brazil	20211-110
3	Hospital Universitario Clementio Fraga Filho	Rio de Janeiro		Brazil

Sponsors and Collaborators

• Johns Hopkins University
• Universidade Federal do Rio de Janeiro

Investigators

• Principal Investigator: Susan Dorman, MD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT00728507
• Other Study ID Numbers: 06-0018
• First Posted: Aug 5, 2008
• Last Update Posted: Apr 20, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Johns Hopkins University: Tuberculosis; Moxifloxacin; Rifapentine
• Additional relevant MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide; Ethambutol; Rifapentine

Study Results

Participant Flow

Arm/Group Title	HPZM	HRZE
Arm/Group Description	Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. 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.	Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. Isoniazid, Rifampin, Pyrazinamide, Ethambutol: Administered per standard of care for TB treatment
Period Title: Overall Study
STARTED	62	59
COMPLETED	60	51
NOT COMPLETED	2	8

Baseline Characteristics

Arm/Group Title	HPZM	HRZE	Total
Arm/Group Description	Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. 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.	Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. Isoniazid, Rifampin, Pyrazinamide, Ethambutol: Administered per standard of care for TB treatment	Total of all reporting groups
Overall Participants	62	59	121
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	33	30	32
Sex: Female, Male (Count of Participants)
Female	47 75.8%	36 61%	83 68.6%
Male	15 24.2%	23 39%	38 31.4%
Region of Enrollment (participants) [Number]
Brazil	62 100%	59 100%	121 100%

Outcome Measures

1. Primary Outcome

Title	To Compare, by Treatment Group, the Percentage of Patients With a Negative Sputum Culture at the End of Intensive Phase Therapy.
Description	LJ culture conversion
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

modified intention to treat population

Arm/Group Title	HPZM	HRZE
Arm/Group Description	Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. 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.	Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. Isoniazid, Rifampin, Pyrazinamide, Ethambutol: Administered per standard of care for TB treatment
Measure Participants	60	51
Number [percentage of participants]	78.3 126.3%	84.3 142.9%

2. Primary Outcome

Title	To Compare the Safety and Tolerability of the 2 Intensive Phase Regimens.
Description	Study was prematurely terminated and data was not collected for this outcome measure.
Time Frame	Weekly or more frequent

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HPZM	HRZE
Arm/Group Description	Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. 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.	Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. Isoniazid, Rifampin, Pyrazinamide, Ethambutol: Administered per standard of care for TB treatment
Measure Participants	0	0

Adverse Events

Arm/Group Title	HPZM		HRZE
Arm/Group Description	Two months of isoniazid, rifapentine, pyrazinamide and moxifloxacin (HPZM) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. 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.		Two months of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) administered once daily. Pyridoxine (vitamin B6) will be given with each dose of isoniazid. Isoniazid, Rifampin, Pyrazinamide, Ethambutol: Administered per standard of care for TB treatment
All Cause Mortality
	HPZM		HRZE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	HPZM		HRZE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/62 (0%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	HPZM		HRZE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/62 (8.1%)		6/59 (10.2%)
Blood and lymphatic system disorders
anemia	0/62 (0%)		1/59 (1.7%)
Eye disorders
change in visual refraction	2/62 (3.2%)		1/59 (1.7%)
Gastrointestinal disorders
nausea	0/62 (0%)		1/59 (1.7%)
General disorders
flu-like syndrome	2/62 (3.2%)		0/59 (0%)
Hepatobiliary disorders
hepatotoxicity	0/62 (0%)		3/59 (5.1%)
Skin and subcutaneous tissue disorders
rash	1/62 (1.6%)		0/59 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.