Trial Outcomes & Findings for A Phase 2 to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonary Tuberculosis. (NCT NCT02193776)

NCT ID: NCT02193776

Last Updated: 2019-07-26

Results Overview

The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP\[0-56\]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

240 participants

Primary outcome timeframe

Day 0 to Day 56 (8 weeks)

Results posted on

2019-07-26

Participant Flow

This trial was conducted at 10 centers in 3 countries (South Africa, Tanzania, and Uganda) from 23 October 2014. Adult male and female participants with drug-sensitive (DS) or multi-drug resistant (MDR) smear-positive pulmonary tuberculosis (TB) were recruited into this open-label multi-center study.

Participants were confirmed positive for M.tuberculosis on molecular test. DS-TB participants were to be sensitive to rifampicin and newly diagnosed with pulmonary TB (or untreated for at least 3 years). MDR-TB participants were to be resistant to rifampicin, sensitive to moxifloxacin and newly diagnosed with pulmonary TB (or treated for \<=7 days).

Participant milestones

Participant milestones
Measure	DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide Participants with DS-TB were randomized to receive 400 milligrams (mg) bedaquiline once daily on Days 1 to 14, 200 mg three times a week (t.i.w) during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kilograms (kg): 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.	MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.
Overall Study STARTED	59	60	61	60
Overall Study Completed Day 70 Follow-up	54	56	60	60
Overall Study Completed Day 140 Follow-up	52	52	58	58
Overall Study COMPLETED	51	53	59	58
Overall Study NOT COMPLETED	8	7	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide Participants with DS-TB were randomized to receive 400 milligrams (mg) bedaquiline once daily on Days 1 to 14, 200 mg three times a week (t.i.w) during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kilograms (kg): 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.	MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.
Overall Study Consent withdrawn	1	0	0	0
Overall Study Failure to comply with protocol	0	1	0	0
Overall Study Investigator/Sponsor decision	1	1	0	0
Overall Study Death	1	0	0	0
Overall Study Adverse event/Specific toxicity	5	5	2	2

Baseline Characteristics

A Phase 2 to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonary Tuberculosis.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide n=59 Participants Participants with DS-TB were randomized to receive 400 mg bedaquiline once daily on Days 1 to 14, 200 mg t.i.w during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide n=60 Participants Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) n=61 Participants Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kg: 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.	MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide n=60 Participants Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	Total n=240 Participants Total of all reporting groups
Age, Continuous	35.1 years STANDARD_DEVIATION 13.03 • n=5 Participants	33.9 years STANDARD_DEVIATION 10.45 • n=7 Participants	33.3 years STANDARD_DEVIATION 8.60 • n=5 Participants	34.0 years STANDARD_DEVIATION 12.68 • n=4 Participants	34.1 years STANDARD_DEVIATION 11.26 • n=21 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	12 Participants n=7 Participants	15 Participants n=5 Participants	17 Participants n=4 Participants	58 Participants n=21 Participants
Sex: Female, Male Male	45 Participants n=5 Participants	48 Participants n=7 Participants	46 Participants n=5 Participants	43 Participants n=4 Participants	182 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Black or African American	46 Participants n=5 Participants	49 Participants n=7 Participants	49 Participants n=5 Participants	53 Participants n=4 Participants	197 Participants n=21 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) More than one race	13 Participants n=5 Participants	11 Participants n=7 Participants	12 Participants n=5 Participants	5 Participants n=4 Participants	41 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: Day 0 to Day 56 (8 weeks)

Population: The modified intention-to-treat analysis population included all participants included in the safety analysis population for whom valid corresponding efficacy data were available. Pyrazinamide resistant participants were excluded from this analysis population (applicable to both participants with DS-TB and MDR-TB).

Outcome measures

Outcome measures
Measure	DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide n=57 Participants Participants with DS-TB were randomized to receive 400 mg bedaquiline once daily on Days 1 to 14, 200 mg t.i.w during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide n=56 Participants Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) n=59 Participants Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kg: 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.	MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide n=37 Participants Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.
Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System	4.878 percentage change in TTP/day Standard Deviation 1.604	5.182 percentage change in TTP/day Standard Deviation 1.466	4.046 percentage change in TTP/day Standard Deviation 1.129	5.194 percentage change in TTP/day Standard Deviation 1.068

SECONDARY outcome

Timeframe: First study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days)

Population: The safety analysis population included all participants who were randomized (for the DS participant population) or assigned (for the MDR participant population) to study drug and received at least 1 administration of study drug.

A TEAE was defined as any AE which started or worsened on or after first study drug administration up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having Day 70 follow-up visit). Drug-related TEAEs were defined as TEAEs for which relationship to study drug was indicated as 'possible', 'probable', 'certain' or missing. TEAEs leading to death were defined as TEAEs resulted 'fatal' outcome. Serious TEAEs were defined as TEAEs for which serious was indicated as 'yes'. TEAEs leading to discontinuation of study drug were defined as TEAEs for which action taken with study drug was indicated as 'study drug stopped'. TEAEs leading to early withdrawal from study were defined as TEAEs resulted study discontinuation. Grade III and IV TEAEs were defined as TEAEs for which severity (DMID grade) was indicated as 'Grade 3 (severe)' and 'Grade 4 (potentially life-threatening)' or missing, respectively.

Outcome measures

Outcome measures
Measure	DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide n=59 Participants Participants with DS-TB were randomized to receive 400 mg bedaquiline once daily on Days 1 to 14, 200 mg t.i.w during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide n=60 Participants Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.	DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) n=61 Participants Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kg: 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.	MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide n=60 Participants Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Any TEAE	50 Participants	45 Participants	44 Participants	57 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Drug-related TEAE	38 Participants	29 Participants	29 Participants	46 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE leading to death	1 Participants	1 Participants	1 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Any serious TEAE	4 Participants	3 Participants	4 Participants	4 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Drug-related serious TEAE	2 Participants	0 Participants	1 Participants	2 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE leading to discontinuation of study drug	6 Participants	5 Participants	2 Participants	2 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE leading to early withdrawal from study	5 Participants	5 Participants	2 Participants	2 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Grade III TEAE	19 Participants	17 Participants	14 Participants	13 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Grade IV TEAE	8 Participants	7 Participants	2 Participants	1 Participants

Adverse Events

DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide

Serious events: 4 serious events

Other events: 50 other events

Deaths: 2 deaths

DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide

Serious events: 3 serious events

Other events: 45 other events

Deaths: 3 deaths

DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol)

Serious events: 4 serious events

Other events: 44 other events

Deaths: 2 deaths

MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide

Serious events: 4 serious events

Other events: 57 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Almari Conradie, Director, Clinical Operations

TB Alliance

Phone: +27 12 991 6328

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER