Shortening Treatment by Advancing Novel Drugs (STAND)

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ClinicalTrials.gov Identifier: NCT02342886

Recruitment Status : Completed

First Posted : January 21, 2015

Results First Posted : March 26, 2019

Last Update Posted : March 26, 2019

Sponsor:

Information provided by (Responsible Party):

Global Alliance for TB Drug Development

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Tuberculosis, Pulmonary, Drug Sensitive Tuberculosis, Pulmonary, Multi Drug-resistant
Interventions	Drug: Moxifloxacin Drug: PA-824 Drug: Pyrazinamide Drug: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination) Drug: HR (rifampicin plus isoniazid combination tablets)
Enrollment	284

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 Details	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...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with MDR-TB received 400 m...
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 ^[1]	57	63	52	59	10
Not Completed	8	8	15	9	3
Reason Not Completed
Treatment non-compliance	1	0	0	1	0
Late exclusion: rifampicin resistance	1	0	0	0	0
Adverse event/specific toxicity	4	3	11	2	1
Lost to Follow-up	1	0	0	0	0
Death	1	2	1	0	1
Withdrawal by Subject	0	1	0	1	0
Investigator/sponsor decision	0	2	0	3	1
Pregnancy	0	0	2	0	0
Late exclusion: pyrazinamide resistance	0	0	1	0	0
Protocol Violation	0	0	0	2	0
[1] Completed Treatment

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...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with MDR-TB received 400 m...	Total of all reporting groups
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 Number of Baseline Participants		65	71	67	68	13	284
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The Safety analysis population included all patients who were randomized (for the DS-TB patients) or assigned (for the MDR-TB patients) to trial medication and who received at least 1 dose of trial medication. Patients were classified according to treatment received.
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	65 participants	71 participants	67 participants	68 participants	13 participants	284 participants
	<=18 years	2 3.1%	2 2.8%	2 3.0%	0 0.0%	0 0.0%	6 2.1%
	Between 18 and 65 years	63 96.9%	67 94.4%	65 97.0%	67 98.5%	13 100.0%	275 96.8%
	>=65 years	0 0.0%	2 2.8%	0 0.0%	1 1.5%	0 0.0%	3 1.1%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	65 participants	71 participants	67 participants	68 participants	13 participants	284 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) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	65 participants	71 participants	67 participants	68 participants	13 participants	284 participants
	Hispanic or Latino	0 0.0%	0 0.0%	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%	0 0.0%	0 0.0%
	Unknown or Not Reported	65 100.0%	71 100.0%	67 100.0%	68 100.0%	13 100.0%	284 100.0%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	65 participants	71 participants	67 participants	68 participants	13 participants	284 participants
Asian		3 4.6%	6 8.5%	6 9.0%	4 5.9%	0 0.0%	19 6.7%
Black or African American		45 69.2%	49 69.0%	45 67.2%	44 64.7%	8 61.5%	191 67.3%
Native Hawaiian or Other Pacific Islander		0 0.0%	0 0.0%	0 0.0%	1 1.5%	0 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 0.0%	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 unasses...
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...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with MDR-TB received 400 m...
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.
Overall Number of Participants Analyzed	57	61	56	60	11
Measure Type: Count of Participants Unit of Measure: Participants
Favorable	38 66.7%	46 75.4%	43 76.8%	52 86.7%	10 90.9%
Unfavorable	19 33.3%	15 24.6%	13 23.2%	8 13.3%	1 9.1%

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	[Not Specified]
	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%.

Method of Estimation	Estimation Parameter	Treatment difference: unfavourable rate
	Estimated Value	9.88
	Confidence Interval	(2-Sided) 95% -4.13 to 23.89
	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 unasses...
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...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with MDR-TB received 400 m...
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.
Overall Number of Participants Analyzed	52	57	47	53	10
Measure Type: Count of Participants Unit of Measure: Participants
Favorable	38 73.1%	46 80.7%	43 91.5%	52 98.1%	10 100.0%
Unfavorable	14 26.9%	11 19.3%	4 8.5%	1 1.9%	0 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	[Not Specified]
	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%.

Method of Estimation	Estimation Parameter	Treatment difference: unfavourable rate
	Estimated Value	6.62
	Confidence Interval	(2-Sided) 95% -2.15 to 15.40
	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...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with DS-TB were randomized...	Patients with MDR-TB received 400 m...
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 (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	4/65 (6.15%)	3/71 (4.23%)	3/67 (4.48%)	2/68 (2.94%)	1/13 (7.69%)
Serious Adverse Events 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 (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	3/65 (4.62%)	8/71 (11.27%)	8/67 (11.94%)	3/68 (4.41%)	3/13 (23.08%)
Cardiac disorders
Cardiac ventricular thrombosis ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Left ventricular dysfunction ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Myocarditis ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Gastrointestinal disorders
Vomiting ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
General disorders
Death ^† 1	0/65 (0.00%)	0/71 (0.00%)	1/67 (1.49%)	0/68 (0.00%)	0/13 (0.00%)
Hepatobiliary disorders
Acute hepatic failure ^† 1	1/65 (1.54%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Hepatotoxicity ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Jaundice ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Immune system disorders
Hypersensitivity ^† 1	1/65 (1.54%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Infections and infestations
Aspergillus infection ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Lymph node Tuberculosis ^† 1	1/65 (1.54%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Nasal candidiasis ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Pneumonia ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Pulmonary Tuberculosis ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	1/68 (1.47%)	0/13 (0.00%)
Urinary tract infection ^† 1	0/65 (0.00%)	0/71 (0.00%)	1/67 (1.49%)	0/68 (0.00%)	0/13 (0.00%)
Injury, poisoning and procedural complications
Soft tissue injury ^† 1	0/65 (0.00%)	0/71 (0.00%)	1/67 (1.49%)	0/68 (0.00%)	0/13 (0.00%)
Intentional overdose ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	1/68 (1.47%)	0/13 (0.00%)
Investigations
Alanine aminotransferase increased ^† 1	0/65 (0.00%)	1/71 (1.41%)	4/67 (5.97%)	0/68 (0.00%)	0/13 (0.00%)
Aspartate aminotransferase increased ^† 1	0/65 (0.00%)	2/71 (2.82%)	3/67 (4.48%)	0/68 (0.00%)	0/13 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anal squamous cell carcinoma ^† 1	0/65 (0.00%)	0/71 (0.00%)	1/67 (1.49%)	0/68 (0.00%)	0/13 (0.00%)
Lung cancer metastatic ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Nervous system disorders
Hepatic encephalopathy ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Seizure ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	1/68 (1.47%)	0/13 (0.00%)
Renal and urinary disorders
Bladder mass ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	0/13 (0.00%)
Reproductive system and breast disorders
Acquired hydrocele ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	1/68 (1.47%)	0/13 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax ^† 1	0/65 (0.00%)	0/71 (0.00%)	1/67 (1.49%)	0/68 (0.00%)	0/13 (0.00%)
Pneumothorax spontaneous ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Pulmonary oedema ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
1 Term from vocabulary, MedDRA v 20.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	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 (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	61/65 (93.85%)	62/71 (87.32%)	63/67 (94.03%)	62/68 (91.18%)	12/13 (92.31%)
Blood and lymphatic system disorders
Anaemia ^† 1	1/65 (1.54%)	1/71 (1.41%)	4/67 (5.97%)	5/68 (7.35%)	0/13 (0.00%)
Lymphadenopathy ^† 1	0/65 (0.00%)	1/71 (1.41%)	1/67 (1.49%)	1/68 (1.47%)	1/13 (7.69%)
Cardiac disorders
Atrial fibrillation ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Ear and labyrinth disorders
Deafness unilateral ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Eye disorders
Visual acuity reduced ^† 1	0/65 (0.00%)	0/71 (0.00%)	4/67 (5.97%)	8/68 (11.76%)	0/13 (0.00%)
Eye pain ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Eyelid haematoma ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Gastrointestinal disorders
Nausea ^† 1	13/65 (20.00%)	11/71 (15.49%)	11/67 (16.42%)	3/68 (4.41%)	2/13 (15.38%)
Vomiting ^† 1	13/65 (20.00%)	8/71 (11.27%)	6/67 (8.96%)	4/68 (5.88%)	2/13 (15.38%)
Diarrhoea ^† 1	14/65 (21.54%)	7/71 (9.86%)	5/67 (7.46%)	3/68 (4.41%)	1/13 (7.69%)
Abdominal pain ^† 1	3/65 (4.62%)	2/71 (2.82%)	5/67 (7.46%)	3/68 (4.41%)	2/13 (15.38%)
Toothache ^† 1	1/65 (1.54%)	2/71 (2.82%)	2/67 (2.99%)	1/68 (1.47%)	1/13 (7.69%)
Infections and infestations
Gastroenteritis ^† 1	2/65 (3.08%)	2/71 (2.82%)	5/67 (7.46%)	2/68 (2.94%)	0/13 (0.00%)
Upper respiratory tract infection ^† 1	2/65 (3.08%)	2/71 (2.82%)	4/67 (5.97%)	1/68 (1.47%)	1/13 (7.69%)
Lower respiratory tract infection ^† 1	1/65 (1.54%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Rhinitis ^† 1	1/65 (1.54%)	0/71 (0.00%)	1/67 (1.49%)	5/68 (7.35%)	0/13 (0.00%)
Fungal skin infection ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	1/68 (1.47%)	1/13 (7.69%)
Furuncle ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	1/68 (1.47%)	1/13 (7.69%)
Injury, poisoning and procedural complications
Skin abrasion ^† 1	0/65 (0.00%)	0/71 (0.00%)	1/67 (1.49%)	0/68 (0.00%)	1/13 (7.69%)
Investigations
Aspartate aminotransferase increased ^† 1	15/65 (23.08%)	10/71 (14.08%)	15/67 (22.39%)	17/68 (25.00%)	1/13 (7.69%)
Alanine aminotransferase increased ^† 1	13/65 (20.00%)	10/71 (14.08%)	14/67 (20.90%)	11/68 (16.18%)	1/13 (7.69%)
Blood uric acid increased ^† 1	15/65 (23.08%)	11/71 (15.49%)	12/67 (17.91%)	8/68 (11.76%)	1/13 (7.69%)
Gamma-glutamyltransferase increased ^† 1	8/65 (12.31%)	11/71 (15.49%)	11/67 (16.42%)	12/68 (17.65%)	0/13 (0.00%)
Blood glucose increased ^† 1	5/65 (7.69%)	2/71 (2.82%)	2/67 (2.99%)	4/68 (5.88%)	0/13 (0.00%)
Blood alkaline phosphatase increased ^† 1	4/65 (6.15%)	1/71 (1.41%)	3/67 (4.48%)	3/68 (4.41%)	0/13 (0.00%)
Protein urine present ^† 1	2/65 (3.08%)	1/71 (1.41%)	2/67 (2.99%)	2/68 (2.94%)	1/13 (7.69%)
Blood urine present ^† 1	0/65 (0.00%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Metabolism and nutrition disorders
Hyperuricaemia ^† 1	20/65 (30.77%)	21/71 (29.58%)	14/67 (20.90%)	22/68 (32.35%)	2/13 (15.38%)
Decreased appetite ^† 1	4/65 (6.15%)	2/71 (2.82%)	2/67 (2.99%)	2/68 (2.94%)	0/13 (0.00%)
Hyperglycaemia ^† 1	2/65 (3.08%)	1/71 (1.41%)	5/67 (7.46%)	0/68 (0.00%)	0/13 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	15/65 (23.08%)	24/71 (33.80%)	19/67 (28.36%)	15/68 (22.06%)	4/13 (30.77%)
Myalgia ^† 1	3/65 (4.62%)	7/71 (9.86%)	1/67 (1.49%)	5/68 (7.35%)	1/13 (7.69%)
Pain in extremity ^† 1	2/65 (3.08%)	1/71 (1.41%)	2/67 (2.99%)	3/68 (4.41%)	1/13 (7.69%)
Musculoskeletal pain ^† 1	0/65 (0.00%)	1/71 (1.41%)	1/67 (1.49%)	2/68 (2.94%)	1/13 (7.69%)
Flank pain ^† 1	1/65 (1.54%)	0/71 (0.00%)	0/67 (0.00%)	1/68 (1.47%)	1/13 (7.69%)
Nervous system disorders
Headache ^† 1	5/65 (7.69%)	6/71 (8.45%)	7/67 (10.45%)	5/68 (7.35%)	2/13 (15.38%)
Dizziness ^† 1	3/65 (4.62%)	4/71 (5.63%)	7/67 (10.45%)	4/68 (5.88%)	2/13 (15.38%)
Neuropathy peripheral ^† 1	1/65 (1.54%)	0/71 (0.00%)	2/67 (2.99%)	4/68 (5.88%)	3/13 (23.08%)
Somnolence ^† 1	4/65 (6.15%)	0/71 (0.00%)	1/67 (1.49%)	2/68 (2.94%)	0/13 (0.00%)
Burning sensation ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Renal and urinary disorders
Haematuria ^† 1	6/65 (9.23%)	3/71 (4.23%)	3/67 (4.48%)	5/68 (7.35%)	1/13 (7.69%)
Proteinuria ^† 1	6/65 (9.23%)	1/71 (1.41%)	3/67 (4.48%)	4/68 (5.88%)	0/13 (0.00%)
Reproductive system and breast disorders
Menometrorrhagia ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis ^† 1	6/65 (9.23%)	8/71 (11.27%)	5/67 (7.46%)	3/68 (4.41%)	2/13 (15.38%)
Pleuritic pain ^† 1	5/65 (7.69%)	4/71 (5.63%)	4/67 (5.97%)	2/68 (2.94%)	4/13 (30.77%)
Pulmonary embolism ^† 1	0/65 (0.00%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	2/13 (15.38%)
Pneumothorax ^† 1	0/65 (0.00%)	0/71 (0.00%)	1/67 (1.49%)	0/68 (0.00%)	1/13 (7.69%)
Skin and subcutaneous tissue disorders
Pruritus generalised ^† 1	2/65 (3.08%)	2/71 (2.82%)	8/67 (11.94%)	11/68 (16.18%)	0/13 (0.00%)
Pruritus ^† 1	3/65 (4.62%)	2/71 (2.82%)	3/67 (4.48%)	5/68 (7.35%)	2/13 (15.38%)
Rash ^† 1	4/65 (6.15%)	2/71 (2.82%)	1/67 (1.49%)	6/68 (8.82%)	1/13 (7.69%)
Rash pruritic ^† 1	1/65 (1.54%)	1/71 (1.41%)	4/67 (5.97%)	2/68 (2.94%)	1/13 (7.69%)
Rash papular ^† 1	1/65 (1.54%)	2/71 (2.82%)	1/67 (1.49%)	2/68 (2.94%)	1/13 (7.69%)
Night sweats ^† 1	1/65 (1.54%)	0/71 (0.00%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
Vascular disorders
Hypotension ^† 1	1/65 (1.54%)	1/71 (1.41%)	0/67 (0.00%)	0/68 (0.00%)	1/13 (7.69%)
1 Term from vocabulary, MedDRA v 20.0 † Indicates events were collected by systematic assessment

Limitations and 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.

There IS 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.

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.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Leandra Lombard, Director, Clinical Operations
Organization:	TB Alliance
Phone:	+27 87 700 3900
EMail:	Leandra.Lombard@tballiance.org

Layout table for additonal information

Responsible Party:	Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier:	NCT02342886
Other Study ID Numbers:	NC-006-(M-PA-Z)
First Submitted:	October 14, 2014
First Posted:	January 21, 2015
Results First Submitted:	February 2, 2019
Results First Posted:	March 26, 2019
Last Update Posted:	March 26, 2019

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