To Evaluate the Safety, Tolerability, and Efficacy of TMC207 as Part of an Individualized Multi-drug Resistant Tuberculosis (MDR-TB) Treatment Regimen in Participants With Sputum Smear-positive Pulmonary MDR-TB.

• Sponsor: Janssen Infectious Diseases BVBA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00910871
• Collaborator: (none)
• Enrollment: 241
• Locations: 27
• Arm: 1
• Duration (Months): 40
• Patients Per Site: 8.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety, tolerability and effectiveness of TMC207 in combination with an individualized background regimen (BR) of antibacterial drugs as treatment for MDR-TB

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: TMC207; Drug: Background Regimen (BR) for MDR-TB	Phase 2

Detailed Description

This is a Phase II, open-label (all people involved know the identity of the intervention) trial to evaluate the safety, tolerability, and efficacy of TMC207 as part of an individualized Multi-drug Resistant Tuberculosis (MDR-TB) treatment regimen in participants with sputum smear-positive pulmonary MDR-TB. Approximately 225 participants will receive TMC207 for 24 weeks in combination with an individualized background regimen (BR) of antibacterial drugs used in the treatment of TB according to national and international guidelines and selected at the baseline visit. TMC207 dosage will be 400 mg once daily (q.d.) for the first 2 weeks and 200 mg 3 times/week (t.i.w.) for the following 22 weeks. Upon completion of the 24-week treatment with TMC207, all participants will continue to receive their BR under the care of their physician and in accordance with national TB program (NTP) treatment guidelines.

Additionally, the pharmacokinetics (how the body absorbs, distributes, metabolizes and eliminates a drug) of TMC207 and its N-monodesmethyl metabolite (M2), and pharmacokinetic/pharmacodynamic (the study of the action or effects a drug has on the body) relationships for safety and efficacy will be assessed. Safety evaluations that will be performed are lab tests, vital signs, ECG, reporting of adverse events, physical examinations and X-rays.

All participants will be followed up for 19 months after their last intake of TMC207. Also participants who prematurely withdraw (unless they withdraw consent) will be followed for this period or until the last follow-up visit for the last patient in the trial. Investigators will be asked to provide information about the survival/clinical outcome of these participants throughout the follow-up period, approximately every 6 months.

Primary outcome is time to sputum culture conversion in Mycobacteria Growth Indicator Tube (MGIT) during and beyond treatment with TMC207. Sputum culture conversion will be defined as 2 consecutive negative cultures from sputa collected at least 28 days apart.

Study Design

• Study Type: Interventional
• Actual Enrollment: 241 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open-label Trial With TMC207 as Part of a Multi-drug Resistant Tuberculosis (MDR-TB) Treatment Regimen in Subjects With Sputum Smear-positive Pulmonary Infection With MDR-TB.
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TMC207 TMC207 400mg once daily for 2 weeks then 200mg three times a week for 22 weeks in addition to Background Regimen (BR) for the treatment of multi-drug resistant tuberculosis (MDR-TB).	Drug: TMC207; TMC207 400mg once daily for 2 weeks then 200mg three times a week for 22 weeks.; Drug: Background Regimen (BR) for MDR-TB; Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as specified in the protocol for up to 96 weeks.

Outcome Measures

Primary Outcome Measures

1. The Median Time to Sputum Culture Conversion [Up to Week 24]

   The table below shows the median time in days to culture conversion for the modified intent-to-treat (mITT) population up to Week 24. Sputum culture conversion is defined as 2 consecutive sputum cultures negative for multi-drug resistant tuberculosis (MDR-TB) taken at least 25 days apart. Participants who discontinued during the 24-week period were considered non-responders (based on Mycobacteria Growth Indicator Tube [MGIT]).

Secondary Outcome Measures

1. The Percentage of Participants With Sputum Culture Conversion [Week 120]

   The table below shows the percentage of participants who were responders to treatment. Sputum culture conversion is defined as 2 consecutive sputum cultures negative for multi-drug resistant tuberculosis (MDR-TB) taken at least 25 days apart. Participants who discontinued or died during the trial were considered non-responders.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Females of child-bearing potential must be using and are willing to continue using effective birth control methods, or be willing to practice sexual abstinence throughout treatment or be nonheterosexual active

• Confirmed pulmonary MDR-TB infection including those infected with XDR (extensively drug resistant)-TB

• Positive for acid-fast bacilli (AFB) on direct smear examination of expectorated sputum specimen (= 1+ smear-positive)

• HIV-positive patients are eligible, provided they meet the requirements as described in the protocol

• Must voluntarily sign the Informed Consent Form (ICF) prior to starting any study activities

• Willing to comply with protocol requirements

• Willing to comply with NTP treatment guidelines

Exclusion Criteria:

• Patients having a known or suspected hypersensitivity or serious adverse reaction to TMC207

• Patients with significant cardiac arrhythmia requiring medication

• Patients with complicated or severe extrapulmonary manifestations of TB, including central nervous system infection

• Patients with certain QT/QTc interval characteristics as described in the protocol

• Patients having participated in other clinical studies with investigational agents, within 8 weeks prior to trial start

• Women who are pregnant or breastfeeding

• Patients who have previously received treatment with TMC207 as part of a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Beijing		China
2		Fuzhou		China
3		Jinan		China
4		Nanjing		China
5		Shanghai		China
6		Talinn		Estonia
7		Tartu		Estonia
8		Nairobi		Kenya
9		Seoul		Korea, Republic of
10		Suwon		Korea, Republic of
11		Stopinu Region		Latvia
12		Callao		Peru
13		Lima		Peru
14		Quezon City		Philippines
15		Arkhangelsk		Russian Federation
16		Moscow		Russian Federation
17		Orel		Russian Federation
18		Bellville West Cape		South Africa
19		Durban		South Africa
20		Sandringham		South Africa
21		Nakhon		Thailand
22		Nonthaburi		Thailand
23		Istanbul		Turkey
24		Kecioren		Turkey
25		Donetsk		Ukraine
26		Kiev		Ukraine
27		Odessa		Ukraine

Sponsors and Collaborators

• Janssen Infectious Diseases BVBA

Investigators

• Study Director: Janssen Infectious Diseases BVBA Clinical Trial, Janssen Infectious Diseases BVBA

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Infectious Diseases BVBA
• ClinicalTrials.gov Identifier: NCT00910871
• Other Study ID Numbers: CR012352; TMC207-TiDP13-C209; 2008-008444-25; NCT00980811
• First Posted: Jun 1, 2009
• Last Update Posted: Apr 24, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by Janssen Infectious Diseases BVBA: Tuberculosis; TMC207-TiDP13-C209; TMC207-C209; TMC207; TB; MDR-TB
• Additional relevant MeSH terms: Tuberculosis; Tuberculosis, Multidrug-Resistant; Bedaquiline

Study Results

Participant Flow

Recruitment Details	A Phase II open label trial with TMC207 as part of multi-drug resistant mycobacterium tuberculosis (MDR-TB) treatment regimen in participants with sputum smear-positive pulmonary infection with MDR-TB.
Pre-assignment Detail	A total of 241 participants were enrolled in the study; 8 participants were withdrawn from the study before study drug administration and 233 started treatment with study drug.

Arm/Group Title	TMC207
Arm/Group Description	Participants will receive 400 milligram (mg) TMC207 tablets orally 2 times a day along with background regimen from Day 1 to Week 2 followed by 200 mg TMC207 tablets orally 3 times a day from Week 3 to Week 24 along with background regimen, then background therapy from Week 25 to end of study (Week 120).
Period Title: Overall Study
STARTED	233
COMPLETED	179
NOT COMPLETED	54

Baseline Characteristics

Arm/Group Title	TMC207
Arm/Group Description	Participants will receive 400 milligram (mg) TMC207 tablets orally 2 times a day along with background regimen from Day 1 to Week 2 followed by 200 mg TMC207 tablets orally 3 times a day from Week 3 to Week 24 along with background regimen, then background therapy from Week 25 to end of study (Week 120).
Overall Participants	233
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.6 (12.1)
Sex: Female, Male (Count of Participants)
Female	83 35.6%
Male	150 64.4%

Outcome Measures

1. Primary Outcome

Title	The Median Time to Sputum Culture Conversion
Description	The table below shows the median time in days to culture conversion for the modified intent-to-treat (mITT) population up to Week 24. Sputum culture conversion is defined as 2 consecutive sputum cultures negative for multi-drug resistant tuberculosis (MDR-TB) taken at least 25 days apart. Participants who discontinued during the 24-week period were considered non-responders (based on Mycobacteria Growth Indicator Tube [MGIT]).
Time Frame	Up to Week 24

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population used for all efficacy analyses included all randomized participants who received at least 1 dose of TMC207 excluding participants with drug-susceptible tuberculosis (DS-TB) or participants that were not evaluable for efficacy.

Arm/Group Title	TMC207
Arm/Group Description	Participants will receive 400 milligram (mg) TMC207 tablets orally 2 times a day along with background regimen from Day 1 to Week 2 followed by 200 mg TMC207 tablets orally 3 times a day from Week 3 to Week 24 along with background regimen, then background therapy from Week 25 to end of study (Week 120).
Measure Participants	205
Median (95% Confidence Interval) [Days]	57

2. Secondary Outcome

Title	The Percentage of Participants With Sputum Culture Conversion
Description	The table below shows the percentage of participants who were responders to treatment. Sputum culture conversion is defined as 2 consecutive sputum cultures negative for multi-drug resistant tuberculosis (MDR-TB) taken at least 25 days apart. Participants who discontinued or died during the trial were considered non-responders.
Time Frame	Week 120

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population used for all efficacy analyses included all randomized participants who received at least 1 dose of TMC207 excluding participants with drug-susceptible tuberculosis (DS-TB) or participants that were not evaluable for efficacy.

Arm/Group Title	TMC207
Arm/Group Description	Participants will receive 400 milligram (mg) TMC207 tablets orally 2 times a day along with background regimen from Day 1 to Week 2 followed by 200 mg TMC207 tablets orally 3 times a day from Week 3 to Week 24 along with background regimen, then background therapy from Week 25 to end of study (Week 120).
Measure Participants	205
Number [Percentage of Participants]	72.2 31%

Adverse Events

Time Frame	Baseline up to Week 120
Adverse Event Reporting Description	Only participants who had at least one of the treatment emergent adverse events (TEAEs) listed in the other (non-serious) adverse events table are included in the total number of participants with non-serious adverse events.
Arm/Group Title	TMC207
Arm/Group Description	Participants will receive 400 milligram (mg) TMC207 tablets orally 2 times a day along with background regimen from Day 1 to Week 2 followed by 200 mg TMC207 tablets orally 3 times a day from Week 3 to Week 24 along with background regimen, then background therapy from Week 25 to end of study (Week 120).
All Cause Mortality
	TMC207
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	TMC207
	Affected / at Risk (%)	# Events
Total	47/233 (20.2%)
Blood and lymphatic system disorders
Anaemia	2/233 (0.9%)
Cardiac disorders
Cardiac failure	1/233 (0.4%)
Cardiac failure congestive	2/233 (0.9%)
Cor pulmonale	1/233 (0.4%)
Ear and labyrinth disorders
Deafness	1/233 (0.4%)
Gastrointestinal disorders
Ileus paralytic	1/233 (0.4%)
Vomiting	1/233 (0.4%)
Alcoholic pancreatitis	1/233 (0.4%)
Gastritis	1/233 (0.4%)
Inguinal hernia	1/233 (0.4%)
General disorders
Treatment failure	2/233 (0.9%)
Hepatobiliary disorders
Cholelithiasis	1/233 (0.4%)
Liver disorder	1/233 (0.4%)
Hepatitis	1/233 (0.4%)
Infections and infestations
Gastroenteritis	1/233 (0.4%)
Lung infection	2/233 (0.9%)
Pneumonia	3/233 (1.3%)
Tuberculosis	6/233 (2.6%)
Hepatitis a	1/233 (0.4%)
Lung abscess	1/233 (0.4%)
Lymph node tuberculosis	1/233 (0.4%)
Pyopneumothorax	1/233 (0.4%)
Injury, poisoning and procedural complications
Concussion	1/233 (0.4%)
Contusion	1/233 (0.4%)
Investigations
Blood glucose fluctuation	1/233 (0.4%)
Electrocardiogram qt prolonged	1/233 (0.4%)
Metabolism and nutrition disorders
Decreased appetite	1/233 (0.4%)
Dehydration	1/233 (0.4%)
Diabetes mellitus inadequate control	1/233 (0.4%)
Hyponatraemia	1/233 (0.4%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/233 (0.4%)
Fistula	1/233 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/233 (0.4%)
Nervous system disorders
Cerebral haemorrhage	1/233 (0.4%)
Ischaemic cerebral infarction	1/233 (0.4%)
Neurotoxicity	1/233 (0.4%)
Psychiatric disorders
Emotional disorder	1/233 (0.4%)
Hallucination	1/233 (0.4%)
Psychiatric symptom	1/233 (0.4%)
Renal and urinary disorders
Renal impairment	1/233 (0.4%)
Ureteric stenosis	1/233 (0.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/233 (0.4%)
Dyspnoea	2/233 (0.9%)
Hydropneumothorax	2/233 (0.9%)
Pneumothorax	5/233 (2.1%)
Cough	1/233 (0.4%)
Haemoptysis	4/233 (1.7%)
Pulmonary bulla	1/233 (0.4%)
Pulmonary haemorrhage	1/233 (0.4%)
Respiratory failure	1/233 (0.4%)
Surgical and medical procedures
Surgery	1/233 (0.4%)
Lung operation	1/233 (0.4%)
Vascular disorders
Hypertension	1/233 (0.4%)
Hypovolaemic shock	1/233 (0.4%)
Other (Not Including Serious) Adverse Events
	TMC207
	Affected / at Risk (%)	# Events
Total	179/233 (76.8%)
Blood and lymphatic system disorders
Anaemia	13/233 (5.6%)
Ear and labyrinth disorders
Tinnitus	18/233 (7.7%)
Gastrointestinal disorders
Diarrhoea	27/233 (11.6%)
Nausea	35/233 (15%)
Vomiting	26/233 (11.2%)
Abdominal pain	14/233 (6%)
Dyspepsia	14/233 (6%)
General disorders
Injection site pain	15/233 (6.4%)
Chest pain	17/233 (7.3%)
Infections and infestations
Nasopharyngitis	17/233 (7.3%)
Upper respiratory tract infection	13/233 (5.6%)
Investigations
Blood uric acid increased	20/233 (8.6%)
Alanine aminotransferase increased	12/233 (5.2%)
Aspartate aminotransferase increased	14/233 (6%)
Hepatic enzyme increased	12/233 (5.2%)
Metabolism and nutrition disorders
Hyperuricaemia	36/233 (15.5%)
Hypokalaemia	19/233 (8.2%)
Decreased appetite	12/233 (5.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	35/233 (15%)
Pain in extremity	16/233 (6.9%)
Nervous system disorders
Dizziness	13/233 (5.6%)
Headache	31/233 (13.3%)
Psychiatric disorders
Insomnia	18/233 (7.7%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	17/233 (7.3%)
Skin and subcutaneous tissue disorders
Pruritus	18/233 (7.7%)
Rash	13/233 (5.6%)

Limitations/Caveats

In Participant Flow, the 12 deaths shown are restricted to those that occurred during the trial and do not include 4 deaths reported after discontinuation in long-term survival follow-up.

More Information

Certain Agreements

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

It is the policy of the sponsor not to allow the investigators to publish their results or findings prior to the sponsor's publication of the overall trial results.The investigator agrees that before he/she publishes any results of this trial, he/she shall provide the sponsor with at least 45 days for full review of the prepublication manuscript prior to submission of the manuscript to the publisher.