STAND: Shortening Treatment by Advancing Novel Drugs

• Sponsor: Global Alliance for TB Drug Development (Other)
• Overall Status: Completed
• CT.gov ID: NCT02342886
• Collaborator: (none)
• Enrollment: 284
• Locations: 26
• Arms: 5
• Actual Duration (Months): 38.9
• Patients Per Site: 10.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis, Pulmonary, Drug Sensitive; Tuberculosis, Pulmonary, Multi Drug-resistant	Drug: Moxifloxacin; Drug: PA-824; Drug: Pyrazinamide; Drug: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination); Drug: HR (rifampicin plus isoniazid combination tablets)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 284 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MDR-TB moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg for 26 weeks.	Drug: Moxifloxacin; Oral; Other Names: BAY 12-8039 Avelox Avalon Avelon ; Drug: PA-824; Oral; Drug: Pyrazinamide; Oral
Active Comparator: DS-TB (HRZE), HR 26 consecutive weeks to DS-TB subjects only, as follows: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination) Weeks 1-8 with daily dose per the subjects weight HR (Rifampicin plus isoniazid combination tablets) Weeks 9 - 26 with daily dose per the subjects weight Daily dose per the subjects weight as follows: 30-39kg: 2 tablets; 40-54kg: 3 tablets; 55 - 70kg: 4 tablets; 71kg and over: 5 tablets.	Drug: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination); Oral; Other Names: Rifafour e-275 ; Drug: HR (rifampicin plus isoniazid combination tablets); Oral
Experimental: DS-TB PA-824 200mg 26 weeks moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once daily for 26 weeks	Drug: Moxifloxacin; Oral; Other Names: BAY 12-8039 Avelox Avalon Avelon ; Drug: PA-824; Oral; Drug: Pyrazinamide; Oral
Experimental: DS-TB PA-824 200mg 17 weeks moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once a day for 17 weeks	Drug: Moxifloxacin; Oral; Other Names: BAY 12-8039 Avelox Avalon Avelon ; Drug: PA-824; Oral; Drug: Pyrazinamide; Oral
Experimental: DS-TB PA-824 100mg 17 weeks moxifloxacin 400 mg + PA-824 100 mg + pyrazinamide 1500 mg orally once daily for 17 weeks	Drug: Moxifloxacin; Oral; Other Names: BAY 12-8039 Avelox Avalon Avelon ; Drug: PA-824; Oral; Drug: Pyrazinamide; Oral

Outcome Measures

Primary Outcome Measures

1. Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Modified Intent to Treat [MITT] Population) [From Day 1 to Month 12.]

   Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following end of treatment (EOT), had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or were dying from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required an extension, restart or change of treatment except for reinfection/pregnancy, or failed to complete adequate treatment who were unassessable at 12 months or lost to follow-up/withdrawn before EOT.

2. Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Per Protocol [PP] Population) [From Day 1 to Month 12.]

   Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following EOT, had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or died from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required a restart or change of treatment because of an unfavorable outcome with or without bacteriological confirmation, ie, on bacteriological, radiographic or clinical grounds.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. MDR-TB treatment arm subjects should be resistant to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid).

2. A chest x-ray which in the opinion of the investigator is compatible with pulmonary TB.

3. 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.

1. 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.

1. 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.

1. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.

2. 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.

1. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.

Specific Treatments

1. Previous treatment with PA-824 as part of a clinical trial.

2. 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.

1. 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.

2. 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).

3. Use of systemic glucocorticoids within one year of start of screening (inhaled or intranasal glucocorticoids are allowed).

4. 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

1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Center for Tuberculosis and Lung Diseases	Tbilisi		Georgia	0101
2	Centre for Respiratory Disease Research (CRDR) Keny Medical Research Institute (KEMRI)	Nairobi		Kenya
3	Centre for Respiratory Disease Research (CRDR) Kenya Medical Research Institute (KEMRI)	Nairobi		Kenya
4	Pusat Perubatan Universiti Kebangsaan	Cheras	Kuala Lumpur	Malaysia
5	Universiti Teknologi MARA	Batu Caves	Selangor	Malaysia
6	Institute of Respiratory Medicine (IPR)	Kuala Lumpur		Malaysia	53000
7	Philippine General Hospital	Ermita	Manila	Philippines	1000
8	Vincent Balang	Pio del Pilar	Manila	Philippines	1230
9	Lung Center of Philippines	Manila		Philippines	1104
10	TASK	Bellville	Cape Town	South Africa	7531
11	University of Cape Town Lung Institute	Mowbray	Cape Town	South Africa	7700
12	Setshaba Research Centre	Pretoria	Gauteng	South Africa
13	The Aurum Institute: Tembisa Hospital Cnr	Tembisa	Gauteng	South Africa	1632
14	CHRU Themba Lethu Clinic	Westdene	Johannesburg	South Africa
15	Durban International Clinical Trials Unit (DbnlCTU)	Durban	KwaZulu-Natal	South Africa	4001
16	Klerksdorp Tshepong Hospital	Klerksdorp	North West Province	South Africa	2571
17	Synexus SA	Mamelodi East	Pretoria	South Africa
18	Madibeng Centre for Research (MCR)	Brits		South Africa	0250
19	THINK: Tuberculosis & HIV Investigative Network of Kwazulu Natal	Durban		South Africa	4001
20	The Aurum Institute	Klerksdorp		South Africa
21	The Aurum Institute: Rustenberg	Rustenburg		South Africa
22	Ifakara Health Institute (IHI)	Dar es Salaam		Tanzania
23	NIMR - Mbeya Medical Research Programme (MMRP)	Mbeya		Tanzania
24	Kilimanjaro National Institute for Medical Research	Mwanza		Tanzania
25	Uganda CWRU Research Collaboration	Kampala		Uganda
26	Centre for Infectious Disease Research in Zambia (CIDRZ)	Lusaka		Zambia

Sponsors and Collaborators

• Global Alliance for TB Drug Development

Investigators

• Principal Investigator: Stephen H Gillespie, MD, University of St Andrews

Study Documents (Full-Text)

• Study Protocol - Apr 14, 2014
• Statistical Analysis Plan - Jan 18, 2017

More Information

Publications

None provided.

• Responsible Party: Global Alliance for TB Drug Development
• ClinicalTrials.gov Identifier: NCT02342886
• Other Study ID Numbers: NC-006-(M-PA-Z)
• First Posted: Jan 21, 2015
• Last Update Posted: Mar 26, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Global Alliance for TB Drug Development: Tuberculosis; Multi Drug-Resistant Tuberculosis; Drug-sensitive Tuberculosis; PA-824; Moxifloxacin; Pyrazinamide; Rifampicin; Isoniazid; Ethambutol; HRZE; HR; Pretomanid; NC-006; STAND
• Additional relevant MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Hypersensitivity; Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide; Ethambutol

Study Results

Participant Flow

Recruitment Details	Adult male and female patients with drug-sensitive (DS) and multi-drug resistant (MDR) smear-positive pulmonary tuberculosis (TB) were recruited into this open-label multicenter study.
Pre-assignment Detail	Patients were confirmed sputum positive for tubercule bacilli on smear microscopy. DS-TB patients were required to be sensitive to rifampicin and newly diagnosed with pulmonary TB (or untreated for at least 3 years). MDR-TB patients were required to be resistant to rifampicin. Both DS and MDR-TB patients could be sensitive/resistant to isoniazid.

Arm/Group Title	DS-TB: 4 Months Moxifloxacin + PA-824 (100 mg) + Pyrazinamide	DS-TB: 4 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	DS-TB: 2 Months HRZE / 4 Months HR	MDR-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide
Arm/Group Description	Patients with DS-TB were randomized to receive 400 milligrams (mg) moxifloxacin + 100 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 150 mg rifampicin + 75 mg isoniazid + 400 mg pyrazinamide + 275 mg ethambutol combination tablets (HRZE) orally once daily from Weeks 1 to 8 during the treatment period. Patients then received 150 mg rifiampicin + 75 mg isoniazid combination tablets (HR) orally once daily from Weeks 9 to 26 during the treatment period. The daily dose of HRZE and HR was calculated based on patients' weight. Patients then entered a follow-up period up to Month 24.	Patients with MDR-TB received 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24.
Period Title: Overall Study
STARTED	65	71	67	68	13
Completed Month 12 Follow-Up	43	52	49	57	10
Completed Month 24 Follow-Up	40	47	46	53	10
COMPLETED	57	63	52	59	10
NOT COMPLETED	8	8	15	9	3

Baseline Characteristics

Arm/Group Title	DS-TB: 4 Months Moxifloxacin + PA-824 (100 mg) + Pyrazinamide	DS-TB: 4 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	DS-TB: 2 Months HRZE / 4 Months HR	MDR-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	Total
Arm/Group Description	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 100 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 150 mg rifampicin + 75 mg isoniazid + 400 mg pyrazinamide + 275 mg ethambutol combination tablets (HRZE) orally once daily from Weeks 1 to 8 during the treatment period. Patients then received 150 mg rifiampicin + 75 mg isoniazid combination tablets (HR) orally once daily from Weeks 9 to 26 during the treatment period. The daily dose of HRZE and HR was calculated based on patients' weight. Patients then entered a follow-up period up to Month 24.	Patients with MDR-TB received 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24.	Total of all reporting groups
Overall Participants	65	71	67	68	13	284
Age (Count of Participants)
<=18 years	2 3.1%	2 2.8%	2 3%	0 0%	0 0%	6 2.1%
Between 18 and 65 years	63 96.9%	67 94.4%	65 97%	67 98.5%	13 100%	275 96.8%
>=65 years	0 0%	2 2.8%	0 0%	1 1.5%	0 0%	3 1.1%
Sex: Female, Male (Count of Participants)
Female	14 21.5%	23 32.4%	23 34.3%	20 29.4%	7 53.8%	87 30.6%
Male	51 78.5%	48 67.6%	44 65.7%	48 70.6%	6 46.2%	197 69.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	65 100%	71 100%	67 100%	68 100%	13 100%	284 100%
Race/Ethnicity, Customized (Count of Participants)
Asian	3 4.6%	6 8.5%	6 9%	4 5.9%	0 0%	19 6.7%
Black or African American	45 69.2%	49 69%	45 67.2%	44 64.7%	8 61.5%	191 67.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	1 1.5%	0 0%	1 0.4%
White	3 4.6%	3 4.2%	3 4.5%	3 4.4%	2 15.4%	14 4.9%
Mixed Race	8 12.3%	12 16.9%	8 11.9%	13 19.1%	3 23.1%	44 15.5%
Other	6 9.2%	1 1.4%	5 7.5%	3 4.4%	0 0%	15 5.3%

Outcome Measures

1. Primary Outcome

Title	Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Modified Intent to Treat [MITT] Population)
Description	Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following end of treatment (EOT), had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or were dying from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required an extension, restart or change of treatment except for reinfection/pregnancy, or failed to complete adequate treatment who were unassessable at 12 months or lost to follow-up/withdrawn before EOT.
Time Frame	From Day 1 to Month 12.

Outcome Measure Data

Analysis Population Description

The MITT population included all randomized patients excluding late screening failures, lost to follow-up/withdrawn patients who were culture negative, pregnancy, accidental death during treatment, death during follow-up without TB relapse evidence, re-infection with new TB strain + missing/contaminated Month 12 sputum sample.

Arm/Group Title	DS-TB: 4 Months Moxifloxacin + PA-824 (100 mg) + Pyrazinamide	DS-TB: 4 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	DS-TB: 2 Months HRZE / 4 Months HR	MDR-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide
Arm/Group Description	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 100 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 150 mg rifampicin + 75 mg isoniazid + 400 mg pyrazinamide + 275 mg ethambutol combination tablets (HRZE) orally once daily from Weeks 1 to 8 during the treatment period. Patients then received 150 mg rifiampicin + 75 mg isoniazid combination tablets (HR) orally once daily from Weeks 9 to 26 during the treatment period. The daily dose of HRZE and HR was calculated based on patients' weight. Patients then entered a follow-up period up to Month 24.	Patients with MDR-TB received 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24. Note: The MDR-TB group was not randomized and not included in the analysis population.
Measure Participants	57	61	56	60	11
Favorable	38 58.5%	46 64.8%	43 64.2%	52 76.5%	10 76.9%
Unfavorable	19 29.2%	15 21.1%	13 19.4%	8 11.8%	1 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide, DS-TB: 2 Months HRZE / 4 Months HR
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was assessed using the upper bound of the two-sided 95% confidence interval (CI) for the difference between the percentage of patients who are classified as having an unfavourable status on the intervention (6 months moxifloxacin + 200 mg PA-824 + pyrazinamide) and the control regimen (2 months HRZE/ 4 months HR). The intervention was considered to be non-inferior to the control arm if the upper bound 95% CI was < 12%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference: unfavourable rate
	Estimated Value	9.88
	Confidence Interval	(2-Sided) 95%; -4.13 to 23.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	(DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide) - (DS-TB: 2 Months HRZE/ 4 Months HR).

2. Primary Outcome

Title	Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Per Protocol [PP] Population)
Description	Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following EOT, had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or died from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required a restart or change of treatment because of an unfavorable outcome with or without bacteriological confirmation, ie, on bacteriological, radiographic or clinical grounds.
Time Frame	From Day 1 to Month 12.

Outcome Measure Data

Analysis Population Description

The PP population consisted of the MITT population, excluding patients who were lost to follow-up/withdrawn, had modified/extended treatment for reasons other than unfavourable therapeutic response, did not receive adequate amount of allocated study regimen and patients with major protocol deviations, unless already classified as unfavourable.

Arm/Group Title	DS-TB: 4 Months Moxifloxacin + PA-824 (100 mg) + Pyrazinamide	DS-TB: 4 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide	DS-TB: 2 Months HRZE / 4 Months HR	MDR-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide
Arm/Group Description	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 100 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24.	Patients with DS-TB were randomized to receive 150 mg rifampicin + 75 mg isoniazid + 400 mg pyrazinamide + 275 mg ethambutol combination tablets (HRZE) orally once daily from Weeks 1 to 8 during the treatment period. Patients then received 150 mg rifiampicin + 75 mg isoniazid combination tablets (HR) orally once daily from Weeks 9 to 26 during the treatment period. The daily dose of HRZE and HR was calculated based on patients' weight. Patients then entered a follow-up period up to Month 24.	Patients with MDR-TB received 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24. Note: The MDR-TB group was not randomized and not included in the analysis population.
Measure Participants	52	57	47	53	10
Favorable	38 58.5%	46 64.8%	43 64.2%	52 76.5%	10 76.9%
Unfavorable	14 21.5%	11 15.5%	4 6%	1 1.5%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide, DS-TB: 2 Months HRZE / 4 Months HR
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was assessed using the upper bound of the two-sided 95% CI for the difference between the percentage of patients who are classified as having an unfavourable status on the intervention (6 months moxifloxacin + 200 mg PA-824 + pyrazinamide) and the control regimen (2 months HRZE/ 4 months HR). The intervention was considered to be non-inferior to the control arm if the upper bound 95% CI was < 12%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference: unfavourable rate
	Estimated Value	6.62
	Confidence Interval	(2-Sided) 95%; -2.15 to 15.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	(DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide) - (DS-TB: 2 Months HRZE/ 4 Months HR).

Adverse Events

Time Frame	Treatment emergent adverse events were collected from Day 1 up to and including 14 days after the last administration of trial medication (up to a maximum of 28 weeks).
Adverse Event Reporting Description	The Safety analysis population included all patients in the randomized/assigned to trial medication population set who received at least 1 dose of trial medication. Patients were classified according to treatment received.
Arm/Group Title	DS-TB: 4 Months Moxifloxacin + PA-824 (100 mg) + Pyrazinamide		DS-TB: 4 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide		DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide		DS-TB: 2 Months HRZE/ 4 Months HR		MDR-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide
Arm/Group Description	Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 100 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.		Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 4 months during the treatment period (from Day 1 to Week 17). Patients then entered a follow-up period up to Month 24.		Patients with DS-TB were randomized to receive 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24.		Patients with DS-TB were randomized to receive 150 mg rifampicin + 75 mg isoniazid + 400 mg pyrazinamide + 275 mg ethambutol combination tablets (HRZE) orally once daily from Weeks 1 to 8 during the treatment period. Patients then received 150 mg rifiampicin + 75 mg isoniazid combination tablets (HR) orally once daily from Weeks 9 to 26 during the treatment period. The daily dose of HRZE and HR was calculated based on patients' weight. Patients then entered a follow-up period up to Month 24.		Patients with MDR-TB received 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily for 6 months during the treatment period (from Day 1 to Week 26). Patients then entered a follow-up period up to Month 24.
All Cause Mortality
	DS-TB: 4 Months Moxifloxacin + PA-824 (100 mg) + Pyrazinamide		DS-TB: 4 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide		DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide		DS-TB: 2 Months HRZE/ 4 Months HR		MDR-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/65 (6.2%)		3/71 (4.2%)		3/67 (4.5%)		2/68 (2.9%)		1/13 (7.7%)
Serious Adverse Events
	DS-TB: 4 Months Moxifloxacin + PA-824 (100 mg) + Pyrazinamide		DS-TB: 4 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide		DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide		DS-TB: 2 Months HRZE/ 4 Months HR		MDR-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/65 (4.6%)		8/71 (11.3%)		8/67 (11.9%)		3/68 (4.4%)		3/13 (23.1%)
Cardiac disorders
Cardiac ventricular thrombosis	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Left ventricular dysfunction	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Myocarditis	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Gastrointestinal disorders
Vomiting	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
General disorders
Death	0/65 (0%)		0/71 (0%)		1/67 (1.5%)		0/68 (0%)		0/13 (0%)
Hepatobiliary disorders
Acute hepatic failure	1/65 (1.5%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Hepatotoxicity	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Jaundice	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Immune system disorders
Hypersensitivity	1/65 (1.5%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Infections and infestations
Aspergillus infection	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Lymph node Tuberculosis	1/65 (1.5%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Nasal candidiasis	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Pneumonia	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Pulmonary Tuberculosis	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		1/68 (1.5%)		0/13 (0%)
Urinary tract infection	0/65 (0%)		0/71 (0%)		1/67 (1.5%)		0/68 (0%)		0/13 (0%)
Injury, poisoning and procedural complications
Soft tissue injury	0/65 (0%)		0/71 (0%)		1/67 (1.5%)		0/68 (0%)		0/13 (0%)
Intentional overdose	0/65 (0%)		0/71 (0%)		0/67 (0%)		1/68 (1.5%)		0/13 (0%)
Investigations
Alanine aminotransferase increased	0/65 (0%)		1/71 (1.4%)		4/67 (6%)		0/68 (0%)		0/13 (0%)
Aspartate aminotransferase increased	0/65 (0%)		2/71 (2.8%)		3/67 (4.5%)		0/68 (0%)		0/13 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anal squamous cell carcinoma	0/65 (0%)		0/71 (0%)		1/67 (1.5%)		0/68 (0%)		0/13 (0%)
Lung cancer metastatic	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Nervous system disorders
Hepatic encephalopathy	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Seizure	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		1/68 (1.5%)		0/13 (0%)
Renal and urinary disorders
Bladder mass	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		0/13 (0%)
Reproductive system and breast disorders
Acquired hydrocele	0/65 (0%)		0/71 (0%)		0/67 (0%)		1/68 (1.5%)		0/13 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/65 (0%)		0/71 (0%)		1/67 (1.5%)		0/68 (0%)		0/13 (0%)
Pneumothorax spontaneous	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Pulmonary oedema	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	DS-TB: 4 Months Moxifloxacin + PA-824 (100 mg) + Pyrazinamide		DS-TB: 4 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide		DS-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide		DS-TB: 2 Months HRZE/ 4 Months HR		MDR-TB: 6 Months Moxifloxacin + PA-824 (200 mg) + Pyrazinamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/65 (93.8%)		62/71 (87.3%)		63/67 (94%)		62/68 (91.2%)		12/13 (92.3%)
Blood and lymphatic system disorders
Anaemia	1/65 (1.5%)		1/71 (1.4%)		4/67 (6%)		5/68 (7.4%)		0/13 (0%)
Lymphadenopathy	0/65 (0%)		1/71 (1.4%)		1/67 (1.5%)		1/68 (1.5%)		1/13 (7.7%)
Cardiac disorders
Atrial fibrillation	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Ear and labyrinth disorders
Deafness unilateral	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Eye disorders
Visual acuity reduced	0/65 (0%)		0/71 (0%)		4/67 (6%)		8/68 (11.8%)		0/13 (0%)
Eye pain	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Eyelid haematoma	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Gastrointestinal disorders
Nausea	13/65 (20%)		11/71 (15.5%)		11/67 (16.4%)		3/68 (4.4%)		2/13 (15.4%)
Vomiting	13/65 (20%)		8/71 (11.3%)		6/67 (9%)		4/68 (5.9%)		2/13 (15.4%)
Diarrhoea	14/65 (21.5%)		7/71 (9.9%)		5/67 (7.5%)		3/68 (4.4%)		1/13 (7.7%)
Abdominal pain	3/65 (4.6%)		2/71 (2.8%)		5/67 (7.5%)		3/68 (4.4%)		2/13 (15.4%)
Toothache	1/65 (1.5%)		2/71 (2.8%)		2/67 (3%)		1/68 (1.5%)		1/13 (7.7%)
Infections and infestations
Gastroenteritis	2/65 (3.1%)		2/71 (2.8%)		5/67 (7.5%)		2/68 (2.9%)		0/13 (0%)
Upper respiratory tract infection	2/65 (3.1%)		2/71 (2.8%)		4/67 (6%)		1/68 (1.5%)		1/13 (7.7%)
Lower respiratory tract infection	1/65 (1.5%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Rhinitis	1/65 (1.5%)		0/71 (0%)		1/67 (1.5%)		5/68 (7.4%)		0/13 (0%)
Fungal skin infection	0/65 (0%)		0/71 (0%)		0/67 (0%)		1/68 (1.5%)		1/13 (7.7%)
Furuncle	0/65 (0%)		0/71 (0%)		0/67 (0%)		1/68 (1.5%)		1/13 (7.7%)
Injury, poisoning and procedural complications
Skin abrasion	0/65 (0%)		0/71 (0%)		1/67 (1.5%)		0/68 (0%)		1/13 (7.7%)
Investigations
Aspartate aminotransferase increased	15/65 (23.1%)		10/71 (14.1%)		15/67 (22.4%)		17/68 (25%)		1/13 (7.7%)
Alanine aminotransferase increased	13/65 (20%)		10/71 (14.1%)		14/67 (20.9%)		11/68 (16.2%)		1/13 (7.7%)
Blood uric acid increased	15/65 (23.1%)		11/71 (15.5%)		12/67 (17.9%)		8/68 (11.8%)		1/13 (7.7%)
Gamma-glutamyltransferase increased	8/65 (12.3%)		11/71 (15.5%)		11/67 (16.4%)		12/68 (17.6%)		0/13 (0%)
Blood glucose increased	5/65 (7.7%)		2/71 (2.8%)		2/67 (3%)		4/68 (5.9%)		0/13 (0%)
Blood alkaline phosphatase increased	4/65 (6.2%)		1/71 (1.4%)		3/67 (4.5%)		3/68 (4.4%)		0/13 (0%)
Protein urine present	2/65 (3.1%)		1/71 (1.4%)		2/67 (3%)		2/68 (2.9%)		1/13 (7.7%)
Blood urine present	0/65 (0%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Metabolism and nutrition disorders
Hyperuricaemia	20/65 (30.8%)		21/71 (29.6%)		14/67 (20.9%)		22/68 (32.4%)		2/13 (15.4%)
Decreased appetite	4/65 (6.2%)		2/71 (2.8%)		2/67 (3%)		2/68 (2.9%)		0/13 (0%)
Hyperglycaemia	2/65 (3.1%)		1/71 (1.4%)		5/67 (7.5%)		0/68 (0%)		0/13 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	15/65 (23.1%)		24/71 (33.8%)		19/67 (28.4%)		15/68 (22.1%)		4/13 (30.8%)
Myalgia	3/65 (4.6%)		7/71 (9.9%)		1/67 (1.5%)		5/68 (7.4%)		1/13 (7.7%)
Pain in extremity	2/65 (3.1%)		1/71 (1.4%)		2/67 (3%)		3/68 (4.4%)		1/13 (7.7%)
Musculoskeletal pain	0/65 (0%)		1/71 (1.4%)		1/67 (1.5%)		2/68 (2.9%)		1/13 (7.7%)
Flank pain	1/65 (1.5%)		0/71 (0%)		0/67 (0%)		1/68 (1.5%)		1/13 (7.7%)
Nervous system disorders
Headache	5/65 (7.7%)		6/71 (8.5%)		7/67 (10.4%)		5/68 (7.4%)		2/13 (15.4%)
Dizziness	3/65 (4.6%)		4/71 (5.6%)		7/67 (10.4%)		4/68 (5.9%)		2/13 (15.4%)
Neuropathy peripheral	1/65 (1.5%)		0/71 (0%)		2/67 (3%)		4/68 (5.9%)		3/13 (23.1%)
Somnolence	4/65 (6.2%)		0/71 (0%)		1/67 (1.5%)		2/68 (2.9%)		0/13 (0%)
Burning sensation	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Renal and urinary disorders
Haematuria	6/65 (9.2%)		3/71 (4.2%)		3/67 (4.5%)		5/68 (7.4%)		1/13 (7.7%)
Proteinuria	6/65 (9.2%)		1/71 (1.4%)		3/67 (4.5%)		4/68 (5.9%)		0/13 (0%)
Reproductive system and breast disorders
Menometrorrhagia	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	6/65 (9.2%)		8/71 (11.3%)		5/67 (7.5%)		3/68 (4.4%)		2/13 (15.4%)
Pleuritic pain	5/65 (7.7%)		4/71 (5.6%)		4/67 (6%)		2/68 (2.9%)		4/13 (30.8%)
Pulmonary embolism	0/65 (0%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		2/13 (15.4%)
Pneumothorax	0/65 (0%)		0/71 (0%)		1/67 (1.5%)		0/68 (0%)		1/13 (7.7%)
Skin and subcutaneous tissue disorders
Pruritus generalised	2/65 (3.1%)		2/71 (2.8%)		8/67 (11.9%)		11/68 (16.2%)		0/13 (0%)
Pruritus	3/65 (4.6%)		2/71 (2.8%)		3/67 (4.5%)		5/68 (7.4%)		2/13 (15.4%)
Rash	4/65 (6.2%)		2/71 (2.8%)		1/67 (1.5%)		6/68 (8.8%)		1/13 (7.7%)
Rash pruritic	1/65 (1.5%)		1/71 (1.4%)		4/67 (6%)		2/68 (2.9%)		1/13 (7.7%)
Rash papular	1/65 (1.5%)		2/71 (2.8%)		1/67 (1.5%)		2/68 (2.9%)		1/13 (7.7%)
Night sweats	1/65 (1.5%)		0/71 (0%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)
Vascular disorders
Hypotension	1/65 (1.5%)		1/71 (1.4%)		0/67 (0%)		0/68 (0%)		1/13 (7.7%)

Limitations/Caveats

Following 3 deaths associated with hepatotoxicity, recruitment was suspended, followed by a partial clinical hold by the United States Food and Drug Association. The hold was removed but the Sponsor permanently stopped recruitment in December 2016.

More Information

Certain Agreements

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

The Investigator or any Sub-Investigator shall submit any oral or written publication or abstract concerning this study to the Sponsor not less than thirty (30) days prior to submission to any journal, other publication or meeting for review and removal of confidential information.