PA-824-CL-007: Phase IIa Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis

• Sponsor: Global Alliance for TB Drug Development (Other)
• Overall Status: Completed
• CT.gov ID: NCT00567840
• Collaborator: (none)
• Enrollment: 69
• Locations: 2
• Arms: 5
• Duration (Months): 4
• Patients Per Site: 34.5
• Patients Per Site Per Month: 8.6

Study Details

Study Description

Brief Summary

The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of PA-824 at 200, 600, 1000 and 1200 mg per day in adult patients with newly diagnosed, uncomplicated, smear positive tuberculosis. A control group will receive standard TB treatment.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Tuberculosis	Drug: PA-824	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase IIa Trial to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of 14 Days' Treatment With Four Oral Doses of PA-824 in Adult Participants With Newly Diagnosed, Uncomplicated, Smear-Positive, Pulmonary Tuberculosis
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Dec 1, 2007
• Actual Study Completion Date: Dec 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 PA-824 200 mg/qd	Drug: PA-824; 200 mg, 600 mg, 100 mg, 1200 mg qd; Other Names: Rifafour e-275
Experimental: 2 PA-824 600 mg/qd	Drug: PA-824; 200 mg, 600 mg, 100 mg, 1200 mg qd; Other Names: Rifafour e-275
Experimental: 3 PA-824 1000 mg/qd	Drug: PA-824; 200 mg, 600 mg, 100 mg, 1200 mg qd; Other Names: Rifafour e-275
Experimental: 4 PA-824 1200 mg/qd	Drug: PA-824; 200 mg, 600 mg, 100 mg, 1200 mg qd; Other Names: Rifafour e-275
Active Comparator: 5 Rifafour e-275 mg	Drug: PA-824; 200 mg, 600 mg, 100 mg, 1200 mg qd; Other Names: Rifafour e-275

Outcome Measures

Primary Outcome Measures

1. Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14). [Day 0 and Day 14]

Secondary Outcome Measures

1. Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2). [Day 0 and Day 2]

2. Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14). [Day 2 and Day 14]

3. EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14) [Day 0 and Day 14]

4. EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2) [Day 0 and Day 2]

5. EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified] [Day 2 and Day 14]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• informed consent

• M/F 18-64 yo

• newly diagnosed pulmonary TB

• sputum positive

• adequate contraception

Exclusion Criteria:

• poor health

• rifampicin resistance

• treatment with other anti TB agents in last 3 mos.

• extrapulmonary TB

• COPD

• neuropathy

• ECG wih QRS prolongation ove 120 msec

• CV disorder

• diabetes requiring insulin

• Metabolic disease

• drug/alcohol abuse

• pregnancy

• use of substances that are strong inhibitors/inducers of CYP450

• use of ARV

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tiervlei Trials Center, Stellenbosch University	Cape Town	Cape Province	South Africa	8000
2	University of Cape Town Lung Institute	Cape Town	Cape Province	South Africa

Sponsors and Collaborators

• Global Alliance for TB Drug Development

Investigators

• Principal Investigator: Rodney Dawson, MD, UCT Lung Institute
• Principal Investigator: Andreas Diacon, MD, Tiervlei Trial Center, Stelennbosch University, South Africa

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00567840
• Other Study ID Numbers: PA-824-CL-007
• First Posted: Dec 5, 2007
• Last Update Posted: May 15, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by , ,: Early Bactericidal Activity; EBA; pulmonary tuberculosis; PA-824; Pretomanid; CL-007
• Additional relevant MeSH terms: Tuberculosis; Tuberculosis, Pulmonary

Study Results

Participant Flow

Arm/Group Title	PA-824 200 mg	PA-824 600 mg	PA-824 1000 mg	PA-824 1200 mg	Rifafour
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days	PA-824: 600 mg per day for 14 consecutive days	PA-824: 1000 mg per day for 14 consecutive days	PA-824: 1200 mg per day for 14 consecutive days	Rifafour e-275 on Days 1 to 14, dosed by weight
Period Title: Overall Study
STARTED	15	15	16	15	8
COMPLETED	13	15	15	14	8
NOT COMPLETED	2	0	1	1	0

Baseline Characteristics

Arm/Group Title	PA-824 200 mg	PA-824 600 mg	PA-824 1000 mg	PA-824 1200 mg	Rifafour	Total
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days	PA-824: 600 mg per day for 14 consecutive days	PA-824: 1000 mg per day for 14 consecutive days	PA-824: 1200 mg per day for 14 consecutive days	Rifafour e-275 on Days 1 to 14, dosed by weight	Total of all reporting groups
Overall Participants	15	15	16	15	8	69
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.5 (8.50)	30.6 (9.72)	31.7 (8.86)	32.4 (11.51)	21.9 (3.44)	30.2 (9.48)
Sex: Female, Male (Count of Participants)
Female	8 53.3%	6 40%	7 43.8%	6 40%	4 50%	31 44.9%
Male	7 46.7%	9 60%	9 56.3%	9 60%	4 50%	38 55.1%
Race/Ethnicity, Customized (Count of Participants)
Black	10 66.7%	6 40%	8 50%	8 53.3%	3 37.5%	35 50.7%
Mixed Ethnic	5 33.3%	9 60%	8 50%	7 46.7%	5 62.5%	34 49.3%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	55.3 (8.58)	55.9 (10.51)	52.5 (9.82)	53.5 (8.48)	48.0 (8.70)	53.6 (9.36)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	20.19 (4.031)	20.09 (3.899)	19.09 (2.562)	19.41 (3.058)	17.53 (1.785)	19.43 (3.294)

Outcome Measures

1. Primary Outcome

Title	Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14).
Time Frame	Day 0 and Day 14

Outcome Measure Data

Analysis Population Description

Some of the EBA values could not be calculated due to missing results. The number of participants given are the number of participants for whom the results were available for this time period and therefore for whom the relevant EBA could be calculated.

Arm/Group Title	PA-824 200 mg	PA-824 600 mg	PA-824 1000 mg	PA-824 1200 mg	Rifafour
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days	PA-824: 600 mg per day for 14 consecutive days	PA-824: 1000 mg per day for 14 consecutive days	PA-824: 1200 mg per day for 14 consecutive days	Rifafour e-275 on Days 1 to 14, dosed by weight
Measure Participants	12	14	15	11	7
Mean (Standard Deviation) [log10 CFU/ml]	0.106 (0.049)	0.107 (0.053)	0.091 (0.083)	0.088 (0.084)	0.148 (0.055)

2. Secondary Outcome

Title	Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2).
Time Frame	Day 0 and Day 2

Outcome Measure Data

Analysis Population Description

Some of the EBA values could not be calculated due to missing results. The number of participants given are the number of participants for whom the results were available for this time period and therefore for whom the relevant EBA could be calculated.

Arm/Group Title	PA-824 200 mg	PA-824 600 mg	PA-824 1000 mg	PA-824 1200 mg	Rifafour
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days	PA-824: 600 mg per day for 14 consecutive days	PA-824: 1000 mg per day for 14 consecutive days	PA-824: 1200 mg per day for 14 consecutive days	Rifafour e-275 on Days 1 to 14, dosed by weight
Measure Participants	15	13	15	15	8
Mean (Standard Deviation) [log10 CFU/ml]	0.109 (0.487)	0.096 (0.226)	0.025 (0.340)	-0.035 (0.420)	0.403 (0.290)

3. Secondary Outcome

Title	Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14).
Time Frame	Day 2 and Day 14

Outcome Measure Data

Analysis Population Description

Some of the EBA values could not be calculated due to missing results. The number of participants given are the number of participants for whom the results were available for this time period and therefore for whom the relevant EBA could be calculated.

Arm/Group Title	PA-824 200 mg	PA-824 600 mg	PA-824 1000 mg	PA-824 1200 mg	Rifafour
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days	PA-824: 600 mg per day for 14 consecutive days	PA-824: 1000 mg per day for 14 consecutive days	PA-824: 1200 mg per day for 14 consecutive days	Rifafour e-275 on Days 1 to 14, dosed by weight
Measure Participants	12	13	14	11	7
Mean (Standard Deviation) [log10 CFU/ml]	0.106 (0.063)	0.113 (0.079)	0.095 (0.062)	0.113 (0.099)	0.112 (0.050)

4. Secondary Outcome

Title	EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14)
Time Frame	Day 0 and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PA-824 200 mg	PA-824 600 mg	PA-824 1000 mg	PA-824 1200 mg	Rifafour
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days	PA-824: 600 mg per day for 14 consecutive days	PA-824: 1000 mg per day for 14 consecutive days	PA-824: 1200 mg per day for 14 consecutive days	Rifafour e-275 on Days 1 to 14, dosed by weight
Measure Participants	12	14	13	12	8
Mean (Standard Deviation) [hours/day]	3.818 (2.327)	4.776 (2.879)	4.865 (3.461)	4.440 (2.169)	9.741 (5.249)

5. Secondary Outcome

Title	EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2)
Time Frame	Day 0 and Day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PA-824 200 mg	PA-824 600 mg	PA-824 1000 mg	PA-824 1200 mg	Rifafour
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days	PA-824: 600 mg per day for 14 consecutive days	PA-824: 1000 mg per day for 14 consecutive days	PA-824: 1200 mg per day for 14 consecutive days	Rifafour e-275 on Days 1 to 14, dosed by weight
Measure Participants	13	13	11	15	8
Mean (Standard Deviation) [hours/day]	1.115 (15.256)	5.788 (12.173)	2.795 (9.230)	1.400 (7.659)	24.125 (12.794)

6. Secondary Outcome

Title	EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified]
Time Frame	Day 2 and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PA-824 200 mg	PA-824 600 mg	PA-824 1000 mg	PA-824 1200 mg	Rifafour
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days	PA-824: 600 mg per day for 14 consecutive days	PA-824: 1000 mg per day for 14 consecutive days	PA-824: 1200 mg per day for 14 consecutive days	Rifafour e-275 on Days 1 to 14, dosed by weight
Measure Participants	11	13	12	12	8
Mean (Standard Deviation) [hours/day]	3.833 (2.954)	5.09 (2.768)	4.069 (1.916)	4.868 (3.224)	7.344 (4.66)

Adverse Events

Arm/Group Title	PA-824 200 mg		PA-824 600 mg		PA-824 1000 mg		PA-824 1200 mg		Rifafour
Arm/Group Description	PA-824: 200 mg per day for 14 consecutive days		PA-824: 600 mg per day for 14 consecutive days		PA-824: 1000 mg per day for 14 consecutive days		PA-824: 1200 mg per day for 14 consecutive days		Rifafour e-275 on Days 1 to 14, dosed by weight
All Cause Mortality
	PA-824 200 mg		PA-824 600 mg		PA-824 1000 mg		PA-824 1200 mg		Rifafour
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	PA-824 200 mg		PA-824 600 mg		PA-824 1000 mg		PA-824 1200 mg		Rifafour
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		0/15 (0%)		0/16 (0%)		0/15 (0%)		1/8 (12.5%)
Respiratory, thoracic and mediastinal disorders
Hemoptysis	1/15 (6.7%)		0/15 (0%)		0/16 (0%)		0/15 (0%)		1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	PA-824 200 mg		PA-824 600 mg		PA-824 1000 mg		PA-824 1200 mg		Rifafour
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/15 (40%)		4/15 (26.7%)		5/16 (31.3%)		7/15 (46.7%)		2/8 (25%)
Blood and lymphatic system disorders
Iron Deficiency Anaemia	0/15 (0%)	0	1/15 (6.7%)	1	0/16 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Cardiac disorders
Atrioventricular Block First Degree	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	0/15 (0%)	0	1/8 (12.5%)	1
Atrioventricular Block Second Degree	1/15 (6.7%)	2	0/15 (0%)	0	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0
Wolff-Parkinson-White Syndrome	1/15 (6.7%)	1	0/15 (0%)	0	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0
Eye disorders
Eye Pruritus	0/15 (0%)	0	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0	0/8 (0%)	0
Gastrointestinal disorders
Nausea	0/15 (0%)	0	0/15 (0%)	0	1/16 (6.3%)	1	2/15 (13.3%)	2	0/8 (0%)	0
Vomiting	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	2/15 (13.3%)	2	0/8 (0%)	0
Abdominal Pain	0/15 (0%)	0	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0
Lip Ulceration	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Toothache	1/15 (6.7%)	1	0/15 (0%)	0	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0
General disorders
Chest Pain	1/15 (6.7%)	1	0/15 (0%)	0	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0
Infections and infestations
Urinary Tract Infection	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Investigations
Electrocardiogram QT corrected Interval Prolonged	0/15 (0%)	0	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0	0/8 (0%)	0
Hepatic Enzyme Increased	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Musculoskeletal and connective tissue disorders
Neck Pain	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Pain in the Extremity	1/15 (6.7%)	1	0/15 (0%)	0	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0
Nervous system disorders
Dizziness	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Dizziness Postural	1/15 (6.7%)	1	0/15 (0%)	0	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0
Psychiatric disorders
Confusional State	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hemoptysis	0/15 (0%)	0	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	0/15 (0%)	0	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0	1/8 (12.5%)	1
Rash	0/15 (0%)	0	1/15 (6.7%)	1	1/16 (6.3%)	2	0/15 (0%)	0	0/8 (0%)	0
Pruritus Generalized	1/15 (6.7%)	1	0/15 (0%)	0	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0
Rash Maculo-Papular	0/15 (0%)	0	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Urticaria	0/15 (0%)	0	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0	0/8 (0%)	0

Limitations/Caveats

[Not Specified]

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.