This study is toevaluate the anti-bacterial activity, safety, and tolerability of TMC207in subjects with sputum smear-positive pulmonary infection withmulti-drug resistant Mycobacterium tuberculosis
- Conditions
- Health Condition 1: null- MDR - Tuberculosis
- Registration Number
- CTRI/2012/03/002513
- Lead Sponsor
- Johnson and Johnson Ltd
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 150
1. Male or female subjects. Females may participate if they are of non-childbearing potential,
if they are using effective non-hormone based birth control methods and are willing to
continue practicing birth control methods as outlined in Section 5.2.4 throughout MDR-TB
treatment, or if they are non-heterosexually active or willing to practice sexual abstinence
throughout MDR-TB treatment.
2. Aged between 18 and 65 years, extremes included.
3. Subjects with newly diagnosed sputum smear-positive pulmonary MDR-TB infection as
defined hereafter, with confirmed resistance to at least both RMP and INH by previous
screening from a TB treatment facility, who are willing to start TB-therapy per the protocol.
Resistance to RMP and INH may be shown by susceptibility culture and/or the rapid screen
tests, i.e., fast plaque and Genotype MTBDR line probe (if resistance to RMP or INH is
based on rapid screen tests, these tests need to be repeated at the screening visit and both
tests must be positive).
Subjects with newly diagnosed MDR-TB are defined as a) subjects with MDR-TB who
have never been treated for TB before, or b) subjects with MDR-TB who have previously
been treated with only first-line TB drugs (INH, RMP, EMB, PZA, or SM).
4. Positive for AFB on direct smear examination of expectorated sputum specimen [greater than or equal to 1+ smear
positive].
5. Subjects with a sputum production of a magnitude that makes ability to produce 10 mL per
night likely.
6. Subjects must consent to HIV-testing unless an HIV-test was performed within 1 month
prior to trial start and documentation can be provided (ELISA and/or Western Blot).
7. Subjects must be willing to discontinue all TB drugs to allow 7 days washout before
baseline assessments and starting treatment with TMC207 or placebo.
8. Subjects having a Quetelet Index (Body Mass Index [BMI]) between 15.0 and 28.0 kg/m2,
extremes included. If the subjects BMI is below 15 kg/m2 or above 28 kg/m2, inclusion can
be discussed with the sponsor.
9. Subjects having signed ICF voluntarily before first trial-related activity.
10. Subjects agree to hospitalization if needed per local standard of care.
1. Previously having been treated for MDR-TB.
Subjects previously treated for MDR-TB are defined as those having received any secondline
TB drug, including any of the following anti-mycobacterials: any aminoglycoside
except streptomycin, any fluoroquinolone, the thioamides prothionamide or ethionamide,
and cycloserine.
2. Having a known or suspected hypersensitivity or serious adverse reaction to the study
medication.
3. Having a current or past history of alcohol and/or drug use that, in the investigators
opinion, would compromise the subjects safety or compliance to the study protocol
procedures.
4. Having a clinically significant active medical condition, which in the opinion of the
investigator would prevent appropriate participation in the trial.
5. Having a significant cardiac arrhythmia that requires medication.
6. HIV infected subjects, a) having a CD4+ count 300 cells/microlitre or b) having received
antiretroviral therapy and/or oral or intravenous antifungal medication within the last
90 days are not eligible for the trial. Also subjects, who, in the opinion of the investigator,
might need to start antiretroviral therapy during the 8-week treatment period of Stage 1 or
the 24-week treatment period of Stage 2, are not eligible for the trial.
7. Subjects with complicated or severe extrapulmonary manifestations of TB or neurological
manifestations of TB.
8. Presence of any concomitant severe illness or rapidly deteriorating health condition,
including immune deficiency that would make implementation of the protocol or
interpretation of the study results difficult, or gastrointestinal disease that might, in the
judgment of the investigator, interfere with the absorption of TMC207.
9. Subjects who, upon the evaluation of their pulmonary disease, will require surgical
procedure for management of their TB within the 8-week treatment period of Stage 1 or the
24-week treatment period of Stage 2.
10. Subjects with the following QT/QTc interval characteristics at screening:
a. A marked prolongation of QT/QTc interval, e.g., repeated demonstration of QTcF
(Fredericia correction) interval 450 ms;
b. A history of additional risk factors for Torsade de Pointe, e.g., heart failure,
hypokalemia, family history of Long QT Syndrome;
c. The use of concomitant medications that prolong the QT/QTc interval listed as
disallowed medication in the study protocol.
11. Subjects with the following toxicities at screening as defined by the enhanced Division of
Microbiology and Infectious Diseases (DMID) adult toxicity table (May 2001):
- Creatinine grade 2 or greater (1.5 times the upper limit of normal [ULN]);
- Pancreatic lipase grade 2 or greater (1.5 times ULN);
- Pancreatic amylase grade 3 or greater (2.00 times ULN);
- Hemoglobin grade 4 (6.5 gm/dL);
- Platelet count grade 3 or greater (less than or equal to 49999/mm3);
- Absolute neutrophil count grade 3 or greater (749/mm3);
- Aspartate aminotransferase (AST) grade 2 or greater (2.5 times ULN);
- Alanine aminotransferase (ALT) grade 2 or greater (2.5 times ULN);
- Alkaline phosphatase (ALP) grade 2 or greater (2.5 times ULN);
- Total bilirubin grade 2 or greater (1.6 times ULN);
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Time to sputum culture conversion during treatment with TMC207 or placebo will be the primary outcome parameter. Sputum culture conversion will be defined as 2 consecutive negative cultures from sputa collected at least 28 days apart. All <br/ ><br>intermediate cultures have to be negative as well. <br/ ><br>Timepoint: Day 1, 7, Week 2, 3, 4, 5,6, 7, 10, 12, 14, 16, 18 <br/ ><br>Week 18, 20, 22, 24, 28, 32, 36, 48, 60, 72, 84, 96, <br/ ><br>Week 104 (Stage 1 only) <br/ ><br>Week 108 & 120 (Stage 2 only) <br/ ><br>
- Secondary Outcome Measures
Name Time Method - Time to sputum culture conversion during the first 6 months - % sputum culture conversion at 2, 6, 12 months, and end - Time to first series of 3 consecutive negative spot sputum samples for smear and for culture -Timepoint: Proportion of subjects sputum smear -ve at 2, 6, 12, and 18 months, and end ; <br/ ><br>- The observed and change from baseline of (log10) CFU counts (all timepoints) - Time to 1, 2, or 3 log decrease in log CFU counts; <br/ ><br>- Conversion rate assessed by MGIT;- Time to positive signal (MGIT); <br/ ><br>- Time to death;