Shortening Treatment by Advancing Novel Drugs

Condition(s) targeted: Tuberculosis, Pulmonary, Drug Sensitive; Tuberculosis, Pulmonary, Multi Drug-resistant

Intervention: Moxifloxacin (Drug); PA-824 (Drug); Pyrazinamide (Drug); HRZE (Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol combination tablet) (Drug); HR (rifampicin plus isoniazid combination tablets) (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Global Alliance for TB Drug Development

Official(s) and/or principal investigator(s):
Stephen H Gillespie, MD, Principal Investigator, Affiliation: University of St Andrews

Overall contact:
Daniel Everitt, MD, Phone: (646) 616-8671, Email: dan.everitt@tballiance.org

The purpose of this study is to assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments with varying doses and treatment lengths from 4 to 6 months in subjects with drug-sensitive (DS) pulmonary TB compared to standard HRZE treatment. This study will also assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments after 6 months of treatment in subjects with multi drug-resistant (MDR) pulmonary TB compared to a combination of moxifloxacin, PA-824, and pyrazinamide treatments in DS-TB subjects.

Official title: A Phase 3 Open-Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of the Combination of Moxifloxacin Plus PA-824 Plus Pyrazinamide After 4 and 6 Months of Treatment in Adult Subjects With Drug-Sensitive Smear-Positive Pulmonary Tuberculosis and After 6 Months of Treatment in Adult Subjects With Multi-Drug Resistant, Smear-Positive Pulmonary Tuberculosis.

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

Primary outcome: Incidence of combined bacteriologic failure or relapse of clinical failure at 12 months from start of therapy.

Secondary outcome:

Incidence of bacteriologic failure or relapse or clinical failure at 24 months from the start of therapy as a confirmatory analysis.

The rate of change in time to culture positivity (TTP) over time in liquid culture MGIT in sputum, represented by the model‐fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time.

Time in days to sputum culture conversion to negative status in liquid culture (MGIT) through the treatment period to be explored as a potential biomarker of definitive outcome.

Proportion of subjects with sputum culture conversion to negative status in liquid culture (MGIT) at 4, 8, 12 and 17 weeks to be explored as a potential biomarker of definitive outcome.

Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, and seriousness, leading to TB related or non-TB related death.

Clinical laboratory safety measurements of hematology and chemistry, including observed and change from baseline.

Trough plasma concentrations will be used to evaluate the effects of baseline subject covariates on trial drug pharmacokinetics and associated bacteriological endpoints.

Minimum inhibitory concentration (MIC) against Moxifloxacin and PA-824

Change from baseline in sperm concentration by group.

Change from baseline in male FSH by group.

Change from baseline in male LH by group.

Change from baseline in male Testosterone by group.

Change from baseline in male Inhibin B by group.

Change from baseline in proportion of total motile sperm by group.

Change from baseline in sperm morphology by group.

Change from baseline in sperm volume by group.

Change from baseline in total sperm numbers by group.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial-related procedures. 2. Male or female, aged 18 years or over. 3. Body weight (in light clothing and no shoes) ≥ 30 kg. 4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD) and World Health Organization (WHO) scale on smear microscopy at the trial laboratory. 5. Drug‐Sensitive TB treatment arms subjects should be:

- sensitive to rifampicin by rapid sputum based test (may be sensitive or

resistant to isoniazid) AND

- either newly diagnosed for TB or have a patient history of being untreated for

at least 3 years after cure from a previous episode of TB. If they are entered into the trial due to being sensitive to rifampicin by rapid sputum based test, however on receipt of the rifampicin resistance testing using an indirect susceptibility test in liquid culture this shows they are rifampicin resistant, they will be:

- Excluded as late exclusions;

- Possibly replaced as determined by the sponsor.

6. MDR‐TB treatment arm subjects should be resistant to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid). 7. A chest x-ray which in the opinion of the investigator is compatible with pulmonary TB. 8. Be of non‐childbearing potential or using effective methods of birth control, as defined below: Non‐childbearing potential:

- Subject ‐ not heterosexually active or practice sexual abstinence; or

- Female subject or male subjects female sexual partner ‐ bilateral oophorectomy,

bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or

- Male subject or female subjects male sexual partner ‐ vasectomised or has had a

bilateral orchidectomy minimally three months prior to screening; Effective birth control methods:

- Double barrier method which can include a male condom, diaphragm, cervical cap, or

female condom; or

- Female subject: Barrier method combined with hormone‐based contraceptives or an

intra‐uterine device for the female patient.

- Male subjects' female sexual partner: Double barrier method or hormone‐based

contraceptives or an intra‐uterine device for the female partner. and are willing to continue practising birth control methods and are not planning to conceive throughout treatment and for 12 weeks (male subjects) or 1 week (female subjects) after the last dose of trial medication or discontinuation from trial medication in case of premature discontinuation. (Note: Hormone‐based contraception alone may not be reliable when taking IMP; therefore, Exclusion Criteria: 1. Any non TB related condition (including myasthenia gravis) where participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments. 2. Being or about to be treated for Malaria. 3. Is critically ill and, in the judgment of the investigator, has a diagnosis likely to result in death during the trial or the follow-up period. 4. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), as judged by the investigator. 5. History of allergy or hypersensitivity to any of the trial IMP or related substances, including known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifampicin antibiotics. 6. For HIV infected subjects any of the following:

- CD4+ count <100 cells/µL;

- Karnofsky score <60%;

- Received intravenous antifungal medication within the last 90 days;

- WHO Clinical Stage 4 HIV disease.

7. Resistant to fluoroquinolones (rapid, sputum - based molecular screening tests). If

they are entered into the trial due to being sensitive to fluoroquinolones by rapid sputum based test, however on receipt of the fluoroquinolones resistance testing using an indirect susceptibility test in liquid culture this shows they are fluoroquinolones resistant, they will be:

- Excluded as late exclusions;

- Possibly replaced as determined by the sponsor.

8. Resistant to pyrazinamide (rapid, sputum - based molecular screening tests).

Drug-Sensitive TB treatment arms subjects may be entered prior to receipt of the

rapid, sputum - based molecular pyrazinamide resistance screening test result. On

receipt of the result, if they are resistant, they will be:

- Excluded as late exclusions;

- Possibly replaced as determined by the sponsor. MDR-TB treatment arm subjects

may not be entered prior to receipt of the rapid, sputum - based molecular

pyrazinamide resistance screening test result showing they are sensitive to pyrazinamide. 9. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial. 10. Subjects with any of the following at screening (per measurements and reading done by Central Electrocardiogram (ECG) where applicable):

- Cardiac arrhythmia requiring medication;

- Prolongation of QT/QTc interval with QTcF (Fridericia correction) >450 ms;

- History of additional risk factors for Torsade de Pointes, (e. g., heart failure,

hypokalemia, family history of Long QT Syndrome);

- Any clinically significant ECG abnormality, in the opinion of the investigator.

11. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening. Specific Treatments 12. Previous treatment with PA-824 as part of a clinical trial. 13. For DS-TB treatment arms: Previous treatment for tuberculosis within 3 years prior to

Day (-9 to - 1)(Screening). Subjects who have previously received isoniazid

prophylactically may be included in the trial as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial. For the MDR-TB Subjects: Previous treatment for MDR-TB, although may have been on a MDR TB treatment regimen for no longer than 7 days at start of screening. Previous treatment for TB includes, but is not limited to, gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 14. Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to allergy to any TB drug, their component or to the IMP. 15. Use of any drug within 30 days prior to randomisation known to prolong QTc interval (including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, sparfloxacin, thioridazine). 16. Use of systemic glucocorticoids within one year of start of screening (inhaled or intranasal glucocorticoids are allowed). 17. Subjects recently started or expected to need to start anti-retroviral therapy (ART) within 1 month after randomization. Subjects may be included who have been on ARTs for greater than 30 days prior to start of screening, or who are expected to start ART greater than 30 days after randomization. Laboratory Abnormalities 18. Subjects with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007), where applicable:

- creatinine grade 2 or greater (>1. 5 times upper limit of normal [ULN]);

- creatinine clearance (CrCl) level less than 30 mLs/min according to the

Cockcroft-Gault Formula;

- haemoglobin grade 4 (<6. 5 g/dL);

- platelets grade 3 or greater (under 50x109 cells/L/ 50 000/mm3);

- serum potassium less than the lower limit of normal for the laboratory. This may

be repeated once;

- aspartate aminotransferase (AST) grade 3 or greater (≥3. 0 x ULN) ;

- alanine aminotransferase (ALT) grade 3 or greater (≥3. 0 x ULN);

- alkaline phosphatase (ALP):

- grade 4 (>8. 0 x ULN) to be excluded;

- grade 3 (≥3. 0 - 8. 0 x ULN) must be discussed with and approved by the

sponsor Medical Monitor;

- total bilirubin:

- 2. 0 x ULN, when other liver functions are in the normal range

- 1. 50 x ULN when accompanied by any increase in other liver function tests

subjects with total bilirubin > 1. 25 x ULN and accompanied by any increase in other liver function tests must be discussed with the sponsor medical monitor before enrollment

Daniel Everitt, MD, Phone: (646) 616-8671, Email: dan.everitt@tballiance.org

Centro de Referencia Helio Fraga - FIOCRUZ, Jacarepagua 27710-552, Brazil; Not yet recruiting
Margareth Maria Dalcolmo, Phone: +552124410392, Email: margareth.dalcolmo@ensp.fiocruz.br
Margareth Maria Dalcolmo, Principal Investigator

Instituto de Pesquisa Clinica Evandro Chagas - FIOCRUZ, Manguinhos 21040-900, Brazil; Not yet recruiting
Valeria Cavalcanti Rolla, Phone: +552124486846, Email: valeria.rolla@ipec.fiocruz.br
Valeria Cavalcanti Rolla, Principal Investigator

Hospital Nossa Senhora da Conceicao, Porto Alegre, Brazil; Not yet recruiting
Breno Santos, Phone: 55-51-3341-5316, Email: breno@ghc.com.br
Breno Santos, Principal Investigator

Beijing Tuberculosis and Thoracic, Beijing 101149, China; Not yet recruiting
Mengqiu Gao, Phone: 86 1089509302, Email: gaomqwdm@aliyun.com
Mengqui Gao, Principal Investigator

Shanghai Pulmonary Hospital, Shanghai, China; Not yet recruiting
Wei Sha, Phone: +8613671758200, Email: 13671758200@126.com
Wei Sha, Principal Investigator

Tianjin TB Control Center, Tianjin 300041, China; Not yet recruiting
Wang Xiexiu, Phone: 86 2227116990, Email: wjsttigo@126.com
Wang Xiexiu, Principal Investigator

National Center for Tuberculosis and Lung Diseases, Tbilisi 0101, Georgia; Not yet recruiting
Leila Goginashvili, Phone: (+995)0322910769, Email: leila.goginashvili@tbgeo.ge
Leila Goginashvili, Principal Investigator

GHESKIO, Port-au-Prince 15627, Haiti; Not yet recruiting
Jean Pape, Phone: 50929401430, Email: jwpape@gheskio.org
Jean Pape, Principal Investigator

Centre for Respiratory Disease Research (CRDR) Keny Medical Research Institute (KEMRI), Nairobi, Kenya; Not yet recruiting
Evans Amukoye, Phone: 254 272 4264 / 5, Email: amukoye@gmail.com
Evans Amukoye, Principal Investigator

Centre for Respiratory Disease Research (CRDR) Kenya Medical Research Institute (KEMRI), Nairobi, Kenya; Recruiting
Videlis Nduba, Phone: 254 72 452 2474, Email: vnduba@gmail.com
Videlis Nduba, Principal Investigator

Kenya AIDS Vaccine Initiative (KAVI), University of Nairobi, Nairobi, Kenya; Not yet recruiting
Omu Anzala, Phone: 254 20 272 5404, Email: OAnzala@kaviuon.org
Omu Anzala, Principal Investigator

Institute of Respiratory Medicine (IPR), Kuala Lumpur 53000, Malaysia; Not yet recruiting
Hj Abdul Razak Abdul Muttalif, Phone: +60340232469, Email: drarm@hotmail.com
Hj Abdul Razak Abdul Muttalif, Principal Investigator

Manhiça Health Reasearch Center, Maputo, Mozambique; Not yet recruiting
Alberto Garcia-Basteiro, Phone: (+258) 21 81 01 81, Ext: 326, Email: alberto.garcia-basteiro@isglobal.org
Alberto Garcia-Basteiro, Principal Investigator

Hospital Nacional Arzo Loayza, LIma, Peru; Withdrawn

Hospital Nacional Dos De Mayo, Lima, Peru; Withdrawn

Instituto de Medicina Tropical, LIma 31, Peru; Not yet recruiting
Eduardo Gotuzzo Herencia, Phone: 5113823398, Email: egotuzzo@gotuzzos.com
Eduardo Gotuzzo Herencia, Principal Investigator

Jr. Putumay 177, San Miguel, Peru; Not yet recruiting
John MacRae Thays, Phone: 511 562 1600, Email: jmacrae@impactaperu.org
John MacRae Thays, Principal Investigator

Lung Center of Philippines, Manila 1104, Philippines; Recruiting
Janice Caoili, Phone: 6326225287, Email: janice.caoili@gmail.com
Janice Caoili, Principal Investigator

Philippine Tuberculosis Society, Inc, Quezon City 1102, Philippines; Not yet recruiting
Elizabeth Cadena, Phone: 6327813755, Email: dagscadena47@yahoo.com
Elizabeth Cadena, Principal Investigator

Arkhangelsk Clinical Antituberculosis Dispensary, Arkhangelsk 163002, Russian Federation; Not yet recruiting
Andrey Maryandyshev, Phone: 78182660564, Email: maryandyshev@mail.ru
Andrey Maryandyshev, Principal Investigator

Ural Research Institute for Phtisiopulmonology, Ekaterinburg 620039, Russian Federation; Not yet recruiting
Sergey Skornjakov, Phone: 79222262444, Email: sns@nm.ru
Sergey Skornjakov, Principal Investigator

Novosibirsk Scientific Research Tuberculosis Institute, Novosibirsk 630040, Russian Federation; Not yet recruiting
Ekaterina Kulchavenya, Phone: 79059357029, Email: bact.nniit@gmail.com
Ekaterina Kulchavenya, Principal Investigator

Madibeng Centre for Research (MCR), Brits 0250, South Africa; Recruiting
Cheryl Louw, Phone: 012 252 1140, Email: celouw.mcr@lantic.net
Cheryl Louw, Principal Investigator

SATVI University of Cape Town, Cape Town, South Africa; Not yet recruiting
Hennie Geldenhuys
Hennie Geldenhuys, Principal Investigator

THINK: Tuberculosis & HIV Investigative Network of Kwazulu Natal, Durban 4000, South Africa; Recruiting
Suzanne van Vuuren, Phone: 031 309 4439, Email: s.vanvuuren@thinksa.org.za
Suzanne van Vuuren, Principal Investigator

The Aurum Institute, Klerksdorp, South Africa; Not yet recruiting
Pearl Selepe, Phone: 087 135 1596, Email: pselepe@auruminstitute.org
Pearl Selepe, Principal Investigator

The Aurum Institute: Rustenberg, Rustenburg, South Africa; Recruiting
William Brumskine, Phone: 087 135 1550, Email: wbrumskine@auruminstitute.org
William Brumskine, Principal Investigator

Ifakara Health Institute (IHI), Dar es Salaam, Tanzania; Not yet recruiting
Francis Mhimbira, Phone: 255 78 872 0976, Email: fmhimbira@ihi.or.tz
Francis Mhimbira, Principal Investigator

NIMR - Mbeya Medical Research Programme (MMRP), Mbeya, Tanzania; Not yet recruiting
Issa Sabi, Phone: 255 25 250 3364, Email: isabi@nimr-mmrc.org
Issa Sabi, Principal Investigator

Kilimanjaro Clinical Research Institute (KCRI), Moshi, Tanzania; Not yet recruiting
Gibson Kibiki, Phone: 255 27 275 4201, Email: g.kibiki@kcri.ac.tz
Gibson Kibiki, Principal Investigator

Kilimanjaro National Institute for Medical Research, Mwanza, Tanzania; Not yet recruiting
George PrayGod, Phone: 255 28 250 3012, Email: gpraygod@yahoo.com
George PrayGod, Principal Investigator

Chest Disease Institute (CDI), Amphoe Muang Nonthaburi, Thailand; Not yet recruiting
Charoen Chuchottaworn, Phone: 662589509, Email: charojnj@hotmail.com
Charoen Chuchottaworn, Principal Investigator

Uganda CWRU Research Collaboration, Kampala, Uganda; Not yet recruiting
Alphonse Okwera, Phone: 256 75 243 7675, Email: a_okwera@mucwru.or.ug
Alphonse Okwera, Principal Investigator

Kyiv City Tuberculosis Hospital #1, Kiev 02091, Ukraine; Recruiting
Vasyl Melnyk, Phone: 380445600899, Email: pulmonology@ukr.net
Vasyl Melnyk, Principal Investigator

National Institute of Phthisiatry and Pulmonology, Kyiv 03680, Ukraine; Not yet recruiting
Svitlana Cherenko, Phone: 380442754133, Email: cherenko@ifp.kiev.ua
Svitlana Cherenko, Principal Investigator

Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia; Not yet recruiting
Stewart Reid, Phone: 260 0211 242/257/8/9, Email: stewart.reid@cidrz.org
Stewart Reid, Principal Investigator

TASK, Bellville, Cape Town 7531, South Africa; Recruiting
Andreas Diacon, Phone: 021 917 1044, Email: ahd@sun.ac.za
Andreas Diacon, Principal Investigator

University of Cape Town Lung Institute, Mombray, Cape Town 7700, South Africa; Recruiting
Rodney Dawson, Phone: 021 406 6850, Email: rodney.dawson@uct.ac.za
Rodney Dawson, Principal Investigator

Hospital Universitário Cassiano Antônio Moraes, Vitoria, Espirito Santo 29042-715, Brazil; Not yet recruiting
Reynaldo Dietze, Phone: +552733357120, Email: rdietze@ndi.ufes.br
Reynaldo Dietze, Principal Investigator

Setshaba Research Centre, Pretoria, Gauteng, South Africa; Recruiting
Mookho Malahleha, Phone: 012 799 2422, Email: mookho@setshaba.org.za

CHRU Themba Lethu Clinic, Westdene, Johannesburg, South Africa; Not yet recruiting
Mohammed Siddeque Rassool, Phone: 011 276 8800, Email: mrassool@witshealth.co.za
Mohammed Siddeque Rassool, Principal Investigator

CHRU Themba Lethu Clinic, Westdene, Johannesburg, South Africa; Not yet recruiting
Francesca Conradie, Phone: 011 276 8800, Email: fconradie@witshealth.co.za
Francesca Conradie, Principal Investigator

Pusat Perubatan Universiti Kebangsaan, Cheras, Kuala Lumpur, Malaysia; Not yet recruiting
Andrea Ban, Phone: 603914566359, Email: andrea.ban@gmail.com
Andrea Ban, Principal Investigator

Durban International Clinical Trials Unit (DbnlCTU), Durban, KwaZulu-Natal 4001, South Africa; Recruiting
Umesh Lalloo, Phone: 031 461 1629 / 30, Email: lalloo@ecarefoundation.com
Umesh Lalloo, Principal Investigator

Philippine General Hospital, Ermita, Manila 1000, Philippines; Not yet recruiting
Regina Berba, Phone: 639985381599, Email: rpberba@gmail.com
Regina Berba, Principal Investigator

Vincent Balang, Pio del Pilar, Manila 1230, Philippines; Recruiting
Vincent Balanang, Phone: 6329246101, Email: vmbalanag@gmail.com
Vincent Balanang, Principal Investigator

Klerksdorp Tshepong Hospital, Jouberton Klerksdorp, North West, South Africa; Recruiting
Ebrahim Variava, Phone: 018 406 3111, Email: variava@worldonline.co.za
Ebrahim Variava, Principal Investigator

Synexus SA, Mamelodi East, Pretoria, South Africa; Not yet recruiting
Tasneem Vally, Phone: 012 812 0469, Email: tasneem.vally@synexus-sa.co.za
Tasneem Vally, Principal Investigator

Universiti Teknologi MARA, Batu Caves, Selangor, Malaysia; Not yet recruiting
Ahmad Izzuanuddin Ismail, Phone: 60361264600, Email: ahmadizuanuddin@yahoo.com
Ahmad Izzuanuddin Ismail, Principal Investigator

The Aurum Institute: Tembisa Hospital Cnr, Orange View, Tembisa, South Africa; Recruiting
Modulakgotla A. Sebe, Phone: 087 135 1684, Email: msebe@auruminstitute.org
Modulakgotla A. Sebe, Principal Investigator

Aurum Institute - Welkom, Bedelia, Welkom, South Africa; Not yet recruiting
James Craig Innes, Phone: 27 87 135 1616, Email: cinnes@auruminstitute.org
James Craig Innes, Principal Investigator

Starting date: February 2015
Last updated: June 22, 2015