Tuberculosis
Conditions
Keywords
Tuberculosis, TMC207-TiDP13-C209, TMC207-C209, TMC207, TB, MDR-TB
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
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.
Interventions
DRUGTMC207
TMC207 400mg once daily for 2 weeks then 200mg three times a week for 22 weeks.
DRUGBackground 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.
Sponsors
Janssen Infectious Diseases BVBA
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
China, Estonia, Kenya, Latvia, Peru, Philippines, Russia, South Africa, South Korea, Thailand, Turkey (Türkiye), Ukraine
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| TMC207 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). | 233 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 12 |
| Overall Study | Lost to Follow-up | 8 |
| Overall Study | Protocol Violation | 11 |
| Overall Study | Subject didn't meet eligibility criteria | 5 |
| Overall Study | Undefined | 1 |
| Overall Study | Withdrawal by Subject | 12 |
Baseline characteristics
| Characteristic | TMC207 |
|---|---|
| Age, Continuous | 34.6 years STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 83 Participants |
| Sex: Female, Male Male | 150 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 179 / 233 |
| serious Total, serious adverse events | 47 / 233 |
Outcome results
Primary
The Median Time to Sputum Culture Conversion
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| TMC207 | The Median Time to Sputum Culture Conversion | 57 Days |
Secondary
The Percentage of Participants With Sputum Culture Conversion
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| TMC207 | The Percentage of Participants With Sputum Culture Conversion | 72.2 Percentage of Participants |