Trial name or title

A randomised comparison of ciprofloxacin, levofloxacin and gatifloxacin for the treatment of adults with tuberculous meningitis

Methods

—

Participants

Inclusion criteria: aged > 14 years; clinical diagnosis of tuberculous meningitis

Exclusion criteria: aged < 15 years; pregnant or breastfeeding; patients in whom the physician believes fluoroquinolones are contraindicated (eg previous adverse reaction); consent of either patient or their relatives not obtained

Interventions

1. Conventional 4‐drug antituberculous chemotherapy (ATC) (comprising of isoniazid, rifampicin, pyrazinamide, and ethambutol)
2. Conventional 4‐drug ATC plus ciprofloxacin
3. Conventional 4‐drug ATC plus levofloxacin
4. Conventional 4‐drug ATC plus gatifloxacin

Outcomes

1. Clinical:
a. fever clearance, coma clearance, date of discharge, death at 2 months, disability or death at 9 months
b. Cerebrospinal fluid pressure, lactate, white cell count, protein, and glucose

2. Microbiological:
a. time to cerebrospinal fluid sterility
b. time to negative amplified tuberculous meningitis direct test (Mycobacterium Tuberculosis Direct [MTD] test: Gen‐probe, California)

Starting date

1 April 2003

Contact information

Dr Guy Thwaites ([email protected]), Oxford University Clinical Research Unit, Vietnam

Notes

Location: Vietnam

Registration number: ISRCTN07062956

Source of funding: The Wellcome Trust (UK)

Trial name or title

A comparative study of the bactericidal and sterilizing activity of three fluoroquinolones: gatifloxacin, moxifloxacin and ofloxacin substituted for ethambutol in the 2 month initial phase of the standard anti‐tuberculosis treatment regimen also containing rifampicin, isoniazid and pyrazinamide (South Africa)

Methods

—

Participants

Inclusion criteria: male/female of 18 to 65 years; weight 38 to 80 kg; recently microscopically diagnosed pulmonary tuberculosis; findings in medical history and physical examination not exceeding grade 2; voluntarily signed informed consent; confirmed negative pregnancy test at the screening visit; willing to use effective contraceptive methods during treatment; normal lab values not exceeding grade 2, except haemoglobin < 6.5 g/dL and potassium < 3.0 mEq/L (> grade 1); consent for a pre‐screening biological test to exclude possible multi‐drug‐resistant tuberculosis (MDR‐TB) and negative MDR‐TB screen test will be a check if pre‐screening biological test is done

Exclusion criteria: history of tuberculosis within the last 3 years; concomitant infection requiring additional anti‐infectious treatment (especially anti‐retroviral medication (ARV)); human immunodeficiency virus (HIV)‐infected patients at World Health Organization stage 4; diabetes mellitus or non‐insulin dependent diabetes mellitus requiring treatment; drug and alcohol abuse; history of drug hypersensitivity and/or active allergic disease; impaired renal, hepatic or gastric function that may interfere with drug absorption, distribution, metabolism, or elimination

Interventions

1. Standard antituberculous treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol)
2. Isoniazid, rifampicin, pyrazinamide, and gatifloxacin
3. Isoniazid, rifampicin, pyrazinamide, and ofloxacin
4. Isoniazid, rifampicin, pyrazinamide, and moxifloxacin

Outcomes

Bactericidal and sterilizing activity

Starting date

25 November 2004

Contact information

Dr T Kanyok ([email protected]), UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Switzerland

Notes

Location: South Africa

Registration number: ISRCTN13670619

Sources of funding: UNICEF‐UNDP‐World Bank‐WHO Special Programme for Research and Training in Tropical Diseases (TDR)

Trial name or title

An international multicentre controlled clinical trial to evaluate high dose RIFApentine and a QUINolone in the treatment of pulmonary tuberculosis

Methods

—

Participants

Inclusion criteria: newly diagnosed pulmonary tuberculosis; 2 sputum specimens positive for tubercle bacilli on direct smear microscopy; either no previous antituberculous chemotherapy, or < 2 weeks of previous chemotherapy; aged 18 years and over; firm home address that is readily accessible for visiting and be intending to remain there during the entire treatment and follow‐up period; willing to agree to participate in the study and to give a sample of blood for HIV testing

Exclusion criteria: any condition (except HIV infection) that may prove fatal during the study period; tuberculous meningitis; pre‐existing nontuberculous disease likely to prejudice the response to, or assessment of, treatment (eg insulin‐dependent diabetes, liver or kidney disease, blood disorders, peripheral neuritis); female and known to be pregnant or breastfeeding; suffering from a condition likely to lead to unco‐operative behaviour such as psychiatric illness or alcoholism; contraindications to any medications in the study regimens; requires anti‐retroviral treatment (ART) at diagnosis; history of prolonged QTc syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during the intensive phase of antituberculous therapy; haemoglobin < 7g/L; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper range; creatinine clearance < 30 mL/min; history of seizures; HIV positive with a CD4 count < 200/mm³; weight < 35 kg

Interventions

1. 2 months of daily ethambutol (E), moxifloxacin (M), rifampicin (R), and pyrazinamide (Z) followed by 2 months of twice weekly moxifloxacin and rifapentine (2EMRZ/2P2M2).
2. 2 months of daily ethambutol, moxifloxacin, rifampicin, and pyrazinamide followed by 4 months of once weekly moxifloxacin and rifapentine (2EMRZ/4P1M1)
3. 2 months of daily ethambutol (E), isoniazid (H), rifampicin (R), and pyrazinamide (Z) followed by 4 months of daily isoniazid and rifampicin (2EHRZ/4HR)

Outcomes

1. Combined rate of failure at the end of treatment and relapse, measured at 18 months
2. Presence of rifamycin monoresistance (RMR) in relapse cultures of HIV‐infected patients, measured at 5, 6, 7, 8, 9, 10, 11, 12, 15, 18 months on the 4‐month arm and 7, 8, 9, 10, 11, 12, 15, 18 months on the 6‐month arm, plus at any unscheduled visit
3. Occurrence of serious adverse events at any time during chemotherapy, recorded as they present themselves throughout the course of the trial
4. Sputum culture results at 2 months after the initiation of chemotherapy, measured at all visits
5. Rate of completion of chemotherapy according to the protocol, measured at all visits
6. Number of observed doses of chemotherapy ingested, measured at all visits
7. Any adverse events, recorded as they present themselves throughout the course of the trial

Starting date

31 July 2007

Contact information

Dr Amina Jindani ([email protected]), Centre for Infection

Department of Cellular and Molecular Medicine

St. George’s University of London, UK

Notes

Location: South Africa, Mozambique, Zimbabwe, Zambia

Registration number: ISRCTN44153044

Source of funding: European and Developing Countries Clinical Trials Partnership (EDCTP) (The Netherlands)

Trial name or title

Controlled comparison of two moxifloxacin containing treatment shortening regimens in pulmonary tuberculosis

Methods

—

Participants

Inclusion criteria: signed written consent or witnessed oral consent in the case of illiteracy, before undertaking any trial related activity; 2 sputum specimens positive for tubercle bacilli on direct smear microscopy at the local laboratory; no previous antituberculous chemotherapy; aged 18 years and over; firm home address that is readily accessible for visiting and willingness to inform the study team of any change of address during the treatment and follow‐up period; agreement to participate in the study and to give a sample of blood for human immunodeficiency virus (HIV) testing; laboratory parameters performed up to 14 days before enrolment; serum aspartate aminotransferase (AST) activity < 3 times the upper limit of normal (ULN); serum total bilirubin level < 2.5 times ULN; creatinine clearance level > 30 mL/min; haemoglobin level of at least 7.0 g/dL; platelet count of at least 50 x 10^9 cells/L; serum potassium > 3.5 mmol/L; negative pregnancy test (women of childbearing potential); pre‐menopausal women must be using a barrier form of contraception or be surgically sterilized or have an intra‐uterine contraceptive device in place

Exclusion criteria: unable to take oral medication; previously enrolled in this study; received any investigational drug in the past 3 months; received an antibiotic active against Mycobacterium tuberculosis in the last 14 days (fluoroquinolones, macrolides, standard antituberculous drugs); any condition that may prove fatal during the first two months of the study period; tuberculous meningitis or other forms of severe tuberculosis with high risk of a poor outcome; pre‐existing non‐tuberculosis disease likely to prejudice the response to, or assessment of, treatment (eg insulin‐dependent diabetes, liver or kidney disease, blood disorders, peripheral neuritis, chronic diarrhoeal disease); pregnant or breast feeding; suffering from a condition likely to lead to unco‐operative behaviour (eg psychiatric illness or alcoholism); contraindications to any medications in the study regimens; known to have congenital or sporadic syndromes of QTc prolongation or receiving concomitant medication reported to increase the QTc interval (eg amiodarone, sotalol, disopyramide, quinidine, procainamide, terfenadine); end stage liver failure (class Child‐Pugh C); uncorrected hypokalaemia; weight < 35 kg; known allergy to any fluoroquinolone antibiotic or history of tendinopathy associated with quinolones; HIV infection with CD4 count < 250 x 10^9/L; patients already receiving anti‐retroviral therapy; patients whose initial isolate is shown to be multiple drug resistant

Interventions

1. 8 weeks of chemotherapy with ethambutol, isoniazid, rifampicin, and pyrazinamide plus the moxifloxacin placebo, followed by 9 weeks of isoniazid and rifampicin plus the moxifloxacin placebo, followed by 9 weeks of isoniazid and rifampicin only
2. 8 weeks of chemotherapy with moxifloxacin, isoniazid, rifampicin, and pyrazinamide plus the ethambutol placebo, followed by 9 weeks of moxifloxacin, isoniazid and rifampicin, followed by 9 weeks of the isoniazid placebo and the rifampicin placebo
3. 8 weeks of chemotherapy with ethambutol, moxifloxacin, rifampicin, and pyrazinamide plus the isoniazid placebo, followed by 9 weeks of moxifloxacin and rifampicin plus the isoniazid placebo, followed by 9 weeks of the isoniazid placebo and the rifampicin placebo

Dosages dependent on patient weight category (all drugs taken orally):
1. Moxifloxacin: 400 mg
2. Rifampicin: ≤ 45 kg ‐ 450 mg; > 45 kg ‐ 600 mg
3. Isoniazid: 300 mg
4. Pyrazinamide: < 40 kg ‐ 25 mg/kg rounded to nearest 500 mg; 40 to 55 kg ‐ 1000 mg; 55 to 75 kg ‐ 1500 mg; > 75 kg ‐ 2000 mg
5. Ethambutol: < 40 kg ‐ 15 mg/kg rounded to nearest 100 mg; 40 to 55 kg ‐ 800 mg; 55 to 75 kg ‐ 1200 mg; > 75 kg ‐ 1600 mg

Outcomes

1. Combined failure of bacteriological cure and relapse within 1 year of completion of therapy
2. Proportion of patients with grade 3 or 4 adverse events according to the World Health Organization grade
3. Proportion of participants culture negative at 8 weeks
4. Time to culture negative sputum
5. Speed of decline of sputum viable count

Starting date

1 June 2007

Contact information

Prof Stephen Gillespie, Centre for Medical Microbiology,

Royal Free and University College Medical School, UK

Notes

Location: Kenya, South Africa, Tanzania, Zambia

Registration number: ISRCTN85595810

Sources of funding: European and Developing Countries Clinical Trials Partnership (EDCTP) (The Netherlands); TB Alliance (USA); Bayer HealthCare Pharmaceuticals (USA); Sanofi‐Aventis (France)

Trial name or title

TBTC Study 28: Evaluation of a moxifloxacin‐based, isoniazid‐sparing regimen for tuberculosis treatment

Methods

—

Participants

Inclusion criteria: suspected pulmonary tuberculosis with acid‐fast bacilli in a stained smear of expectorated or induced sputum. Patients whose sputum cultures do not grow M. tuberculosis and those having an M. tuberculosis isolate resistant to (one or more) isoniazid, rifampin, fluoroquinolones, will be discontinued from the study, but followed for 14 days to detect late toxicities from study therapy. Patients having extra‐pulmonary manifestations of tuberculosis, in addition to smear‐positive pulmonary disease, are eligible for enrolment. Sputum must be expectorated or induced; smear results from respiratory secretions obtained by bronchoalveolar lavage or bronchial wash may not be used for assessment of study eligibility; willingness to have HIV testing performed, if HIV serostatus is not known or if the last documented negative HIV test was more than 6 months before enrolment. HIV testing does not need to be repeated if there is written documentation of a positive test (positive ELISA and Western Blot or a plasma HIV‐RNA level > 5000 copies/mL) at any time in the past; 7 or fewer days of multidrug therapy for tuberculosis disease in the 6 months preceding enrolment; 7 or fewer days of fluoroquinolone therapy in the 3 months preceding enrolment; age > 18 years; Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs); signed informed consent; women with child‐bearing potential must agree to practice an adequate (barrier) method of birth control or to abstain from heterosexual intercourse during study therapy; serum amino aspartate transferase (AST) activity ≤ 3 times upper limit of normal; serum total bilirubin level ≤ 2.5 times upper limit of normal; serum creatinine level ≤ 2 times upper limit of normal; complete blood count with hemoglobin level of at least 7.0 g/dL; complete blood count with platelet count of at least 50,000/mm ³ ; serum potassium > 3.5 meq/L; negative pregnancy test (women of childbearing potential)

Exclusion criteria: breastfeeding; known intolerance to any of the study drugs; known allergy to any fluoroquinolone antibiotic; concomitant disorders or conditions for which moxifloxacin (MXF), isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or ethambutol (EMB) are contraindicated (including severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis); current or planned therapy during the intensive phase of therapy using drugs having unacceptable interactions with rifampin (rifabutin can be substituted for rifampin during the continuation phase of therapy); current or planned antiretroviral therapy during intensive phase of therapy; history of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during the intensive phase of therapy; pulmonary silicosis; central nervous system tuberculosis

Interventions

1. Moxifloxacin (with rifampin, pyrazinamide, and ethambutol)
2. Isoniazid (with rifampin, pyrazinamide, and ethambutol)

Outcomes

1. Culture‐conversion rate at the end of the intensive phase of therapy
2. Safety and tolerability
3. Time to culture‐conversion using data from 2‐, 4‐, 6‐, and 8‐week cultures
4. Proportion of patients with any Grade 3 or 4 adverse reactions
5. Adverse events and 2‐month culture conversion rates among HIV‐infected patients vs. HIV‐uninfected patients
6. Rates of treatment failure
7. Delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 8 weeks of moxifloxacin therapy)

Starting date

February 2006

Contact information

Richard E Chaisson (Study Chair), Johns Hopkins University, USA

Notes

Location: Brazil, Canada (Manitoba, Quebec), South Africa, Spain, Uganda, USA (Arkansas, California, Colorado, Washington DC, Georgia, Illinois, Maryland, Massachusetts, New Jersey, New York, North Carolina, Tennessee, Texas, Washington)

Registration number: NCT00144417

Sponsors and collaborators: Centers for Disease Control and Prevention; Global Alliance for TB Drug Development; Bayer

Trial name or title

A controlled trial of a 4‐month quinolone‐containing regimen for the treatment of pulmonary tuberculosis

Methods

—

Participants

Inclusion criteria: male or female; aged 18 to 65 years; currently suffering from recently diagnosed microscopically proven pulmonary tuberculosis and providing informed consent for inclusion in the study

Exclusion criteria: history of tuberculosis treatment within the last 3 years; history of diabetes mellitus or noninsulin dependent diabetes mellitus requiring treatment; concomitant infection requiring additional anti‐infective treatment (especially anti‐retroviral therapy); HIV‐ infected patients with WHO stage 3 infection ‐ except those presenting with only the "loss of weight>10% body weight" criterion ‐ and all HIV infected patients at WHO stage 4

Interventions

1. 4‐month gatifloxacin‐containing antituberculous regimen
2. Standard antituberculous regimen

Outcomes

1. Percentage of relapses by 24 months following treatment cure
2. Percentage of adverse events
3. Time to relapse
4. Percentage of smear and culture conversion at 8 weeks
5. Percentage of patient cured at the end 6. of treatment
7. Time to a composite "unsatisfactory" endpoint
8. Distribution of type and grading of adverse events

Starting date

January 2005

Contact information

Christian Lienhardt (Study Director), Institut de Recherche pour le Developpement, France

Notes

Location: Benin, Guinea, Kenya, Senegal, South Africa

Registration number: NCT00216385

Sponsors and collaborators: Institut de Recherche pour le Developpement; World Health Organization;
European Commission

Trial name or title

Randomized, open label, multiple dose Phase I study of the early bactericidal activity of linezolid, gatifloxacin, levofloxacin, and moxifloxacin in HIV‐non‐infected adults with Initial episodes of sputum smear‐positive pulmonary tuberculosis (DMID 01‐553)

Methods

—

Participants

Inclusion criteria: adults, male or female, aged 18 to 65 years; women with child‐bearing potential (not surgically sterilized or postmenopausal for < 1 year) must be using or agree to use an adequate method of birth control (condom: intravaginal spermicide (foams, jellies, sponge) and diaphragm: cervical cap or intrauterine device) during study drug treatment; newly diagnosed sputum smear‐positive pulmonary tuberculosis as confirmed by sputum AFB smear and chest x‐ray findings consistent with pulmonary tuberculosis; willing and able to provide informed consent; reasonably normal hemoglobin (≥ 8 gm/dL), renal function (serum creatinine < 2 mg/dL), hepatic function (serum AST < 1.5 times the upper limit of normal for the testing laboratory and total bilirubin < 1.3 mg/dL), and random blood glucose < 150 mg/dL

Exclusion criteria: HIV infection; weight < 75% of ideal body weight; presence of significant hemoptysis; patients who cough up frank blood (more than blood streaked sputum); pregnant or breastfeeding women and those who are not practicing birth control; significant respiratory impairment (respiratory rate > 35/min); clinical suspicion of dissemated tuberculosis or tuberculosis meningitis; presence of serious underlying medical illness (eg such as liver failure, renal failure, diabetes mellitus, chronic alcoholism, decompensated heart failure, haematologic malignancy) or patients receiving myelosuppressive chemotherapy; patients receiving any of monoamine oxidase inhibitors (phenelzine, tranylcypromine), adrenergic/serotonergic agonists such as pseudoephedrine and phenylpropanolamine (frequently found in cold and cough remedies), tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, doxepin, amoxapine, etc), antipsychotics (eg chlorpromazine and buspirone), serotonin re‐uptake inhibitors (fluoxetine, paroxetine, sertaline, etc), buproprion, agents known to prolong the QTc interval [erythromycin, clarithromycin, astemizole, type Ia (quinidine, procainamide, disopyramide) and III (amiodarone, sotalol) anti‐arrhythmics, carbamazepine, insulin, sulfonylureas, and meperidine; presence of QTc prolongation (> 450 msec) on baseline EKG; allergy or contraindication to use of study drugs; treatment with antituberculous medications or other antibiotics with known activity against Mycobacterium tuberculosis during the preceding 6 months; inability to provide informed consent; total white blood cell count < 3000/mm³; platelet count < 150,000/mm³; patients with suspected drug‐resistant tuberculosis (eg contact to source patient with drug‐resistant tuberculosis, patients who have relapsed after previous treatment for tuberculosis); patients likely, in the opinion of the local investigator, to be unable to comply with the requirements of the study protocol

Interventions

Participants will be randomized to receive gatifloxacin, levofloxacin, moxifloxacin, or isoniazid (control), and after these arms are enrolled, they will be randomized to receive either linezolid (600 mg once daily) or linezolid (600 mg twice daily) or isoniazid (control). After the initial treatment, all participants will receive 6 months of standard antituberculous treatment outside of the hospital

Outcomes

1. Early bactericidal activity
2. Extended early bactericidal activity
3. Safety evaluations including clinical examination, complete blood counts, and serum total bilirubin, aspartate aminotransferase, and creatinine, and urinalysis will be followed to monitor for drug toxicity

Starting date

February 2004

Contact information

John Johnson ([email protected])

Notes

Location: University of Espírito Santo, Vitória, Brazil

Registration number: NCT00396084

Sponsors: National Institute of Allergy and Infectious Diseases (NIAID)