TMC207-TiDP13-C208: Anti-bacterial Activity, Safety, and Tolerability of TMC207 in Participants With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB).
Sponsor
Janssen Infectious Diseases BVBA (Industry)
Overall Status
Completed
CT.gov ID
NCT00449644
Collaborator
(none)
208
16
4
64
13
0.2
Study Details
Study Description
Brief Summary
The objective of this study is to demonstrate that the antibacterial activity of TMC207 is better than placebo when added to a standardized Background Regimen (BR) for treatment of multi-drug resistant TB. Also safety and tolerability will be evaluated.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
The trial will be conducted in 2 consecutive stages, an exploratory (investigative) stage (Stage 1) and a proof of effectiveness stage (Stage 2). During Stage 1, a panel of 50 participants will be randomized (participants are assigned different treatments based on chance) to receive either TMC207 or placebo for 8 weeks on top of a BR. In Stage 2, another panel of 150 participants will be randomized to receive either TMC207 or placebo for 24 weeks on top of a BR. TMC207 will be dosed as 400 mg every day for the first 2 weeks, and as 200 mg 3 times/week for the following 6 or 22 weeks during Stages 1 and 2, respectively. When the participants in Stage 1 have completed 8 weeks double-blind (neither theparticipant nor the physician knows whether drug or placebo is being taken, or at what dosage) treatment with TMC207 or placebo (or have discontinued earlier), the primary Stage 1 analysis will be performed on all data of the first 8 weeks of treatment. Following this Stage 1 analysis, Stage 2 will be initiated and a panel of 150 new participants will be enrolled. After the double-blind treatment phase in both Stage 1 and Stage 2, participants will continue to receive MDR-TB treatment as per national treatment guidelines. They will be followed for safety, tolerability, pharmacokinetics, and microbiological efficacy for 96 weeks after receiving their last dose of TMC207 or placebo. The Data Safety Monitoring Board Committee will review these data on a regular basis. The DSMB/DSMC is a group of experts in tuberculosis and clinical trial conduct who have no commercial interests in the development of TMC207 and the company (Tibotec, BVBA) that is developing the new TB drug.
Study Design
Study Type:
Interventional
Actual Enrollment
:
208 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase II, Placebo-controlled, Double-blind, Randomized Trial to Evaluate the Anti-bacterial Activity, Safety, and Tolerability of TMC207 in Subjects With Newly Diagnosed Sputum Smear-positive Pulmonary Infection With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB).
Study Start Date
:
Jun 1, 2007
Actual Primary Completion Date
:
Mar 1, 2010
Actual Study Completion Date
:
Oct 1, 2012
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: TMC207 Stage 1 TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 weeks in addition to Background Regimen (BR) for multi-drug resistant tuberculosis (MDR-TB). |
Drug: TMC207
TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 or 22 weeks.
Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)
Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.
|
| Placebo Comparator: Placebo Stage 1 Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 weeks in addition to BR for MDR-TB. |
Drug: Placebo
Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 or 22 weeks.
Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)
Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.
|
| Experimental: TMC207 Stage 2 TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 22 weeks in addition to BR for MDR-TB. |
Drug: TMC207
TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 or 22 weeks.
Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)
Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.
|
| Placebo Comparator: Placebo Stage 2 Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 22 weeks in addition to BR for MDR-TB. |
Drug: Placebo
Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 or 22 weeks.
Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)
Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.
|
Outcome Measures
Primary Outcome Measures
- The Time to Sputum Culture Conversion at Week 8 (Stage 1) [Week 8, Stage 1]
The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.
- The Time to Sputum Culture Conversion at Week 24 (Stage 2) [Week 24, Stage 2]
The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.
Secondary Outcome Measures
- The Time to Sputum Culture Conversion at Week 24 (Stage 1) [Week 24, Stage 1]
The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.
- The Time to Sputum Culture Conversion at Week 72 (Stage 2) [Week 72, Stage 2]
The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment.
- The Percentage of Participants With Sputum Culture Conversion (Stage 1) [Week 8, 24, and 104 (Stage 1)]
The table below shows the percentage of participants in Stage 1 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders.
- The Percentage of Participants With Sputum Culture Conversion (Stage 2) [Week 24, Week 72, and Week 120 (Stage 2)]
The table below shows the percentage of participants in Stage 2 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Females of non-childbearing potential
-
Patients with newly diagnosed sputum smear-positive pulmonary MDR-TB infection
-
Patients must consent to HIV-testing
-
Patients must be willing to discontinue all TB drugs to allow 7 days washout
-
Patients having normal weight
-
Patients are willing to be hospitalized per standard of care.
Exclusion Criteria:
-
Previously having been treated for MDR-TB
-
Having a significant cardiac arrhythmia that requires medication
-
For HIV infected patients, having a CD4+ count < 300 cells/µL
-
Patients with complicated or severe extrapulmonary manifestations of TB or neurological manifestations of TB
-
Patients who will require surgical procedure for management of their TB
-
Evidence of chorioretinitis, optic neuritis, or uveitis at screening
-
Having had a drug susceptibility test performed prior to screening and being not susceptible to at least 3 of the 5 classes of TB drugs used to treat MDR-TB
-
Women who are pregnant and/or breastfeeding.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Rio De Janeiro | Brazil | |||
| 2 | Chennai | India | |||
| 3 | New Delhi | India | |||
| 4 | Stopinu Region | Latvia | |||
| 5 | Lima | Peru | |||
| 6 | Quezon City | Philippines | |||
| 7 | Moscow | Russian Federation | |||
| 8 | Bethelsdorp | South Africa | |||
| 9 | Cape Town | South Africa | |||
| 10 | Durban | South Africa | |||
| 11 | George | South Africa | |||
| 12 | Klerksdorp | South Africa | |||
| 13 | Sandringham | South Africa | |||
| 14 | Chiang Mai | Thailand | |||
| 15 | Nakhon | Thailand | |||
| 16 | Nonthaburi | Thailand |
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:
NCT00449644
Other Study ID Numbers:
- CR011929
- TMC207-TIDP13-C208
- 2007-004462-40
- NCT00614627
- NCT00980265
First Posted:
Mar 20, 2007
Last Update Posted:
Apr 29, 2014
Last Verified:
Apr 1, 2014
Keywords provided by Janssen Infectious Diseases BVBA
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | This trial consisted of an exploratory stage (Stage 1) and a proof-of-efficacy stage (Stage 2). Different participants were enrolled in each stage. Participants in Stage 2 who met protocol-specified criteria were offered open-label treatment with TMC207 after Week 24 (ie, rollover arm). |
|---|---|
| Pre-assignment Detail | A total of 208 participants were randomized and 207 (47 participants in Stage 1 and 160 participants in Stage 2) started treatment with placebo or TMC207 (1 participant did not receive study drug). One placebo participant in Stage 2 rolled-over to treatment with TMC207 after Week 24. |
| Arm/Group Title | TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) |
|---|---|---|---|---|
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 24. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 24. |
| Period Title: Overall Study | ||||
| STARTED | 23 | 24 | 79 | 81 |
| Rollover | 0 | 0 | 0 | 1 |
| COMPLETED | 13 | 11 | 50 | 49 |
| NOT COMPLETED | 10 | 13 | 29 | 32 |
Baseline Characteristics
| Arm/Group Title | TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 24. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 24. | Total of all reporting groups |
| Overall Participants | 23 | 24 | 79 | 81 | 207 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
35.6
(11.66)
|
33.6
(11.04)
|
36.2
(13.13)
|
35.8
(11.01)
|
35.7
(11.88)
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
5
21.7%
|
7
29.2%
|
27
34.2%
|
32
39.5%
|
71
34.3%
|
| Male |
18
78.3%
|
17
70.8%
|
52
65.8%
|
49
60.5%
|
136
65.7%
|
Outcome Measures
| Title | The Time to Sputum Culture Conversion at Week 8 (Stage 1) |
|---|---|
| Description | The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment. |
| Time Frame | Week 8, Stage 1 |
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 study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy. |
| Arm/Group Title | TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) |
|---|---|---|
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: 200 mg TMC207 three times a week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 8. |
| Measure Participants | 21 | 23 |
| Median (95% Confidence Interval) [Days] |
51
|
NA
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0034 |
| Comments | ||
| Method | Cox proportional hazards model | |
| Comments | Treatment, lung cavitation and pooled center were used as covaritates. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 11.77 | |
| Confidence Interval |
(2-Sided) 95% 2.26 to 61.23 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | The Time to Sputum Culture Conversion at Week 24 (Stage 2) |
|---|---|
| Description | The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment. |
| Time Frame | Week 24, Stage 2 |
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 study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy. |
| Arm/Group Title | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) |
|---|---|---|
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 24. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 24. |
| Measure Participants | 66 | 66 |
| Median (95% Confidence Interval) [Days] |
83
|
125
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | ||
| Method | Cox proportional hazards model | |
| Comments | Treatment, lung cavitation and pooled center were used as covaritates. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 2.44 | |
| Confidence Interval |
(2-Sided) 95% 1.57 to 3.80 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | The Time to Sputum Culture Conversion at Week 24 (Stage 1) |
|---|---|
| Description | The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment. |
| Time Frame | Week 24, Stage 1 |
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 study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy. |
| Arm/Group Title | TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) |
|---|---|---|
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: 200 mg TMC207 three times a week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 8. |
| Measure Participants | 21 | 23 |
| Median (95% Confidence Interval) [Days] |
70
|
126
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0022 |
| Comments | ||
| Method | Cox-proportional hazards model | |
| Comments | Treatment, lung cavitation and pooled center were used as covaritates. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 3.14 | |
| Confidence Interval |
(2-Sided) 95% 1.51 to 6.53 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | The Time to Sputum Culture Conversion at Week 72 (Stage 2) |
|---|---|
| Description | The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment. |
| Time Frame | Week 72, Stage 2 |
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 study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy. |
| Arm/Group Title | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) |
|---|---|---|
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 24. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 24. |
| Measure Participants | 66 | 66 |
| Median (95% Confidence Interval) [Days] |
86
|
168
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | MGIT negative (Responders) | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0290 |
| Comments | ||
| Method | Cox proportional hazards model | |
| Comments | Treatment, lung cavitation and pooled center were used as covaritates. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.65 | |
| Confidence Interval |
(2-Sided) 95% 1.05 to 2.59 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | The Percentage of Participants With Sputum Culture Conversion (Stage 1) |
|---|---|
| Description | The table below shows the percentage of participants in Stage 1 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders. |
| Time Frame | Week 8, 24, and 104 (Stage 1) |
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 study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy. |
| Arm/Group Title | TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) |
|---|---|---|
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: 200 mg TMC207 three times a week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week. |
| Measure Participants | 21 | 23 |
| Week 8 |
47.6
207%
|
8.7
36.3%
|
| Week 24 |
81.0
352.2%
|
65.2
271.7%
|
| Week 104 (Stage 1 Trial End) |
52.4
227.8%
|
43.5
181.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | Week 8 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.003 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Treatment as covariate | |
| Method of Estimation | Estimation Parameter | Risk Difference (RD) |
| Estimated Value | 38.9 | |
| Confidence Interval |
(2-Sided) 95% 13.97 to 63.88 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 12.38 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | Week 24 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.237 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Treatment as covariate | |
| Method of Estimation | Estimation Parameter | Risk Difference (RD) |
| Estimated Value | 15.7 | |
| Confidence Interval |
(2-Sided) 95% -10.70 to 42.17 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 13.12 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | Week 104 (Stage 1 Trial End) | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5564 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Treatment as covariate | |
| Method of Estimation | Estimation Parameter | Risk Difference (RD) |
| Estimated Value | 8.9 | |
| Confidence Interval |
(2-Sided) 95% -21.37 to 39.18 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 15.02 |
|
| Estimation Comments | ||
| Title | The Percentage of Participants With Sputum Culture Conversion (Stage 2) |
|---|---|
| Description | The table below shows the percentage of participants in Stage 2 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders. |
| Time Frame | Week 24, Week 72, and Week 120 (Stage 2) |
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 study drug and did not have extensively drug resistant tuberculosis (XDR-TB) or non-multi-drug resistant tuberculosis (non-MDR-TB) at the start of the trial and were evaluable for efficacy. |
| Arm/Group Title | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) |
|---|---|---|
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: 200 mg TMC207 three times a week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 8. |
| Measure Participants | 66 | 66 |
| Week 24 |
78.8
342.6%
|
57.6
240%
|
| Week 72 |
71.2
309.6%
|
56.1
233.8%
|
| Week 120 |
62.1
270%
|
43.9
182.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | Week 24 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.008 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Treatment as covariate | |
| Method of Estimation | Estimation Parameter | Risk Difference (RD) |
| Estimated Value | 21.2 | |
| Confidence Interval |
(2-Sided) 95% 5.59 to 36.83 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 7.90 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | Week 72 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.069 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Treatment as covariate | |
| Method of Estimation | Estimation Parameter | Risk Difference (RD) |
| Estimated Value | 15.2 | |
| Confidence Interval |
(2-Sided) 95% -1.21 to 31.51 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 8.27 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | TMC207 / BR (Stage 1), Placebo / BR (Stage 1) |
|---|---|---|
| Comments | Week 120 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.035 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Treatment as covariate | |
| Method of Estimation | Estimation Parameter | Risk Difference (RD) |
| Estimated Value | 18.2 | |
| Confidence Interval |
(2-Sided) 95% 1.28 to 35.08 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 8.54 |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | Stage 1: Adverse Events were collected from 05-Jun-2007 to 04-Dec-2009. Stage 2: Adverse events were collected from 23-Apr-2008 to 31-Jan-2012. | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Treatment-Emergent Adverse Events (TEAE) from overall treatment phase are reported. Only patients who had at least one of the TEAEs are listed in the Other (non Serious) Adverse Event table are included in the total number of patients with Non-Serious Adverse Events. | |||||||
| Arm/Group Title | TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) | ||||
| Arm/Group Description | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 8: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 8. | Weeks 1 and 2: 400 mg TMC207 once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: 200 mg TMC207 three times per week administered as 2 tablets, and BR. Only BR after Week 24. | Weeks 1 and 2: Placebo once daily administered as 4 tablets, and Background Regimen (BR) for Multi-drug resistant tuberculosis (MDR-TB). Week 3 to 24: Placebo three times per week administered as 2 tablets, and BR. Only BR after Week 24. | ||||
All Cause Mortality |
||||||||
| TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
| TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/23 (4.3%) | 1/24 (4.2%) | 18/79 (22.8%) | 15/81 (18.5%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Lymphadenopathy mediastinal | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Ear and labyrinth disorders | ||||||||
| Conductive deafness | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Abdominal pain | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Pancreatitis acute | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Immune system disorders | ||||||||
| Hypersensitivity | 0/23 (0%) | 0/24 (0%) | 0/79 (0%) | 1/81 (1.2%) | ||||
| Infections and infestations | ||||||||
| Bronchiectasis | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Pneumonia | 0/23 (0%) | 0/24 (0%) | 2/79 (2.5%) | 0/81 (0%) | ||||
| Pulmonary tuberculosis | 0/23 (0%) | 0/24 (0%) | 2/79 (2.5%) | 1/81 (1.2%) | ||||
| Pyothorax | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Tuberculosis | 0/23 (0%) | 0/24 (0%) | 2/79 (2.5%) | 3/81 (3.7%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Alcohol poisoning | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Drug toxicity | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Humerus fracture | 0/23 (0%) | 0/24 (0%) | 0/79 (0%) | 1/81 (1.2%) | ||||
| Pelvic fracture | 0/23 (0%) | 0/24 (0%) | 0/79 (0%) | 1/81 (1.2%) | ||||
| Soft tissue injury | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Diabetic ketoacidosis | 1/23 (4.3%) | 0/24 (0%) | 0/79 (0%) | 0/81 (0%) | ||||
| Nervous system disorders | ||||||||
| Cerebrovascular accident | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Hemiparesis | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Pregnancy, puerperium and perinatal conditions | ||||||||
| Abortion spontaneous | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 1/81 (1.2%) | ||||
| Psychiatric disorders | ||||||||
| Suicidal ideation | 0/23 (0%) | 0/24 (0%) | 1/79 (1.3%) | 0/81 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Haemoptysis | 0/23 (0%) | 0/24 (0%) | 2/79 (2.5%) | 1/81 (1.2%) | ||||
| Pneumothorax | 0/23 (0%) | 1/24 (4.2%) | 0/79 (0%) | 1/81 (1.2%) | ||||
| Pulmonary cavitation | 0/23 (0%) | 0/24 (0%) | 0/79 (0%) | 1/81 (1.2%) | ||||
| Surgical and medical procedures | ||||||||
| Surgery | 0/23 (0%) | 0/24 (0%) | 0/79 (0%) | 4/81 (4.9%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| TMC207 / BR (Stage 1) | Placebo / BR (Stage 1) | TMC207 / BR (Stage 2) | Placebo / BR (Stage 2) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 21/23 (91.3%) | 23/24 (95.8%) | 75/79 (94.9%) | 75/81 (92.6%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 0/23 (0%) | 0/24 (0%) | 6/79 (7.6%) | 3/81 (3.7%) | ||||
| Ear and labyrinth disorders | ||||||||
| Deafness | 1/23 (4.3%) | 1/24 (4.2%) | 5/79 (6.3%) | 4/81 (4.9%) | ||||
| Deafness bilateral | 3/23 (13%) | 3/24 (12.5%) | 5/79 (6.3%) | 7/81 (8.6%) | ||||
| Deafness unilateral | 3/23 (13%) | 5/24 (20.8%) | 10/79 (12.7%) | 7/81 (8.6%) | ||||
| Ear pain | 0/23 (0%) | 0/24 (0%) | 4/79 (5.1%) | 3/81 (3.7%) | ||||
| Tinnitus | 0/23 (0%) | 0/24 (0%) | 3/79 (3.8%) | 11/81 (13.6%) | ||||
| Eye disorders | ||||||||
| Visual acuity reduced | 0/23 (0%) | 0/24 (0%) | 5/79 (6.3%) | 2/81 (2.5%) | ||||
| Gastrointestinal disorders | ||||||||
| Abdominal pain | 0/23 (0%) | 2/24 (8.3%) | 6/79 (7.6%) | 6/81 (7.4%) | ||||
| Abdominal pain upper | 1/23 (4.3%) | 1/24 (4.2%) | 10/79 (12.7%) | 8/81 (9.9%) | ||||
| Constipation | 1/23 (4.3%) | 1/24 (4.2%) | 4/79 (5.1%) | 0/81 (0%) | ||||
| Diarrhoea | 3/23 (13%) | 1/24 (4.2%) | 5/79 (6.3%) | 15/81 (18.5%) | ||||
| Dyspepsia | 1/23 (4.3%) | 1/24 (4.2%) | 4/79 (5.1%) | 12/81 (14.8%) | ||||
| Gastritis | 0/23 (0%) | 0/24 (0%) | 9/79 (11.4%) | 16/81 (19.8%) | ||||
| Nausea | 6/23 (26.1%) | 1/24 (4.2%) | 32/79 (40.5%) | 30/81 (37%) | ||||
| Vomiting | 1/23 (4.3%) | 3/24 (12.5%) | 23/79 (29.1%) | 22/81 (27.2%) | ||||
| General disorders | ||||||||
| Chest pain | 0/23 (0%) | 2/24 (8.3%) | 10/79 (12.7%) | 8/81 (9.9%) | ||||
| Fatigue | 0/23 (0%) | 0/24 (0%) | 6/79 (7.6%) | 1/81 (1.2%) | ||||
| Injection site pain | 0/23 (0%) | 0/24 (0%) | 9/79 (11.4%) | 10/81 (12.3%) | ||||
| Non-cardiac chest pain | 2/23 (8.7%) | 2/24 (8.3%) | 2/79 (2.5%) | 0/81 (0%) | ||||
| Pain | 0/23 (0%) | 0/24 (0%) | 2/79 (2.5%) | 6/81 (7.4%) | ||||
| Pyrexia | 0/23 (0%) | 1/24 (4.2%) | 8/79 (10.1%) | 7/81 (8.6%) | ||||
| Infections and infestations | ||||||||
| Influenza | 1/23 (4.3%) | 0/24 (0%) | 6/79 (7.6%) | 9/81 (11.1%) | ||||
| Nasopharyngitis | 0/23 (0%) | 1/24 (4.2%) | 11/79 (13.9%) | 4/81 (4.9%) | ||||
| Pharyngitis | 0/23 (0%) | 1/24 (4.2%) | 6/79 (7.6%) | 5/81 (6.2%) | ||||
| Urinary tract infection | 0/23 (0%) | 0/24 (0%) | 5/79 (6.3%) | 2/81 (2.5%) | ||||
| Investigations | ||||||||
| Alanine aminotransferase increased | 0/23 (0%) | 0/24 (0%) | 4/79 (5.1%) | 1/81 (1.2%) | ||||
| Aspartate aminotransferase increased | 0/23 (0%) | 0/24 (0%) | 5/79 (6.3%) | 2/81 (2.5%) | ||||
| Blood uric acid increased | 1/23 (4.3%) | 2/24 (8.3%) | 5/79 (6.3%) | 3/81 (3.7%) | ||||
| Transaminases increased | 0/23 (0%) | 0/24 (0%) | 5/79 (6.3%) | 0/81 (0%) | ||||
| Weight decreased | 0/23 (0%) | 0/24 (0%) | 3/79 (3.8%) | 5/81 (6.2%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Anorexia | 0/23 (0%) | 1/24 (4.2%) | 9/79 (11.4%) | 6/81 (7.4%) | ||||
| Hyperuricaemia | 4/23 (17.4%) | 3/24 (12.5%) | 20/79 (25.3%) | 27/81 (33.3%) | ||||
| Hypokalaemia | 0/23 (0%) | 0/24 (0%) | 4/79 (5.1%) | 3/81 (3.7%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 4/23 (17.4%) | 3/24 (12.5%) | 29/79 (36.7%) | 22/81 (27.2%) | ||||
| Back pain | 0/23 (0%) | 3/24 (12.5%) | 9/79 (11.4%) | 8/81 (9.9%) | ||||
| Musculoskeletal pain | 1/23 (4.3%) | 0/24 (0%) | 4/79 (5.1%) | 4/81 (4.9%) | ||||
| Myalgia | 0/23 (0%) | 1/24 (4.2%) | 6/79 (7.6%) | 7/81 (8.6%) | ||||
| Pain in extremity | 2/23 (8.7%) | 4/24 (16.7%) | 2/79 (2.5%) | 3/81 (3.7%) | ||||
| Nervous system disorders | ||||||||
| Dizziness | 3/23 (13%) | 2/24 (8.3%) | 11/79 (13.9%) | 11/81 (13.6%) | ||||
| Headache | 2/23 (8.7%) | 2/24 (8.3%) | 23/79 (29.1%) | 18/81 (22.2%) | ||||
| Neuropathy peripheral | 0/23 (0%) | 0/24 (0%) | 4/79 (5.1%) | 2/81 (2.5%) | ||||
| Paraesthesia | 0/23 (0%) | 0/24 (0%) | 4/79 (5.1%) | 4/81 (4.9%) | ||||
| Psychiatric disorders | ||||||||
| Depression | 0/23 (0%) | 0/24 (0%) | 3/79 (3.8%) | 7/81 (8.6%) | ||||
| Insomnia | 0/23 (0%) | 1/24 (4.2%) | 13/79 (16.5%) | 10/81 (12.3%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough | 0/23 (0%) | 0/24 (0%) | 7/79 (8.9%) | 8/81 (9.9%) | ||||
| Dyspnoea | 0/23 (0%) | 1/24 (4.2%) | 3/79 (3.8%) | 6/81 (7.4%) | ||||
| Dyspnoea exertional | 0/23 (0%) | 0/24 (0%) | 4/79 (5.1%) | 0/81 (0%) | ||||
| Haemoptysis | 3/23 (13%) | 4/24 (16.7%) | 15/79 (19%) | 13/81 (16%) | ||||
| Pharyngolaryngeal pain | 1/23 (4.3%) | 2/24 (8.3%) | 1/79 (1.3%) | 4/81 (4.9%) | ||||
| Pleuritic pain | 2/23 (8.7%) | 0/24 (0%) | 2/79 (2.5%) | 5/81 (6.2%) | ||||
| Rhinorrhoea | 0/23 (0%) | 0/24 (0%) | 4/79 (5.1%) | 0/81 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Acne | 1/23 (4.3%) | 2/24 (8.3%) | 0/79 (0%) | 2/81 (2.5%) | ||||
| Pruritus | 2/23 (8.7%) | 2/24 (8.3%) | 11/79 (13.9%) | 15/81 (18.5%) | ||||
| Rash | 2/23 (8.7%) | 4/24 (16.7%) | 6/79 (7.6%) | 4/81 (4.9%) | ||||
Limitations/Caveats
In Participant Flow, deaths occurring during the trial are reported. In addition, 1 TMC207 and 2 placebo subjects in stage 1 and 4 TMC207 and 1 placebo subject in stage 2 died after discontinuation during 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.
Results Point of Contact
| Name/Title | Medical Leader |
|---|---|
| Organization | Janssen Infectious Diseases - Diagnostics BVBA |
| Phone | 1 609 730-7768 |
Responsible Party:
Janssen Infectious Diseases BVBA
ClinicalTrials.gov Identifier:
NCT00449644
Other Study ID Numbers:
- CR011929
- TMC207-TIDP13-C208
- 2007-004462-40
- NCT00614627
- NCT00980265
First Posted:
Mar 20, 2007
Last Update Posted:
Apr 29, 2014
Last Verified:
Apr 1, 2014