Early Access of TMC207 in Patients With Extensively Drug Resistant or Pre-XDR Pulmonary Tuberculosis

Overview

The purpose of this is a study to provide early access of TMC207 to patients with pulmonary infection due to strains of Mycobacterium tuberculosis (M. tuberculosis) with resistance to isoniazid (INH), rifampin (RMP), and to a fluoroquinolone (FQ) and/or injectable second line tuberculosis (TB) drug (kanamycin, amikacin, or capreomycin) and who are unable/ineligible to participate in any other TMC207 study. In addition, information on safety and tolerability of TMC207 in combination with anti-TB drugs will be assessed and the results of microbiology assessments which are recommended to be performed during the early access study will be collected.

TMC207 is being investigated for the treatment of TB. TB is a contagious bacterial infection caused by M. tuberculosis that commonly affects the lungs, but can also affect other organs. Treatment of TB is protracted and burdensome and is further complicated by the emergence of multi-drug resistant M. tuberculosis strains. TMC207 is a diarylquinoline investigational compound that offers a novel mechanism of anti-TB action by specifically inhibiting mycobacterial adenosine triphosphate (ATP)-synthase. Multi-drug resistant TB (MDR-TB) is defined as infection with a strain of M. tuberculosis that is resistant to both INH and RMP (also known as rifampicin), two important drugs used to treat drug susceptible TB. Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB with additional resistance to the most important second-line TB drugs, ie, one of the injectables (kanamycin, amikacin, or capreomycin) and fluoroquinolones. Pre-XDR TB is defined as MDR-TB with additional resistance to either a FQ or an injectable (kanamycin, amikacin, or capreomycin), but not to both a FQ and an injectable. Patients with either XDR-TB or pre-XDR will be included in this early access study. Patients who qualify for the study will be provided with a 24-week regimen of TMC207 which will be administered along with their background regimen (BR). BR drugs will be provided by the site investigator or designated study personnel in accordance with national TB program (NTP) guidelines. The BR should be constructed with at least 3 anti-tuberculosis drugs to which the patient's infection is known to be susceptible from recent drug susceptibility testing (DST) results (within the previous 6 months) or likely to be susceptible, based on known treatment history. The selection of the BR, including the number of companion drugs for TMC207, will be the responsibility of the investigator. At the screening visit, a completed inclusion/exclusion checklist list will be sent to the sponsor or its representative together with the patient's recent smear or culture and DST results (within preceding 6 months) and laboratory safety results to confirm eligibility. At baseline, a chest X-ray (CXR) will be taken in case no CXR or results of other imaging of the lungs are available within the previous month. Once treatment has been initiated, patients will be instructed to follow the visit schedule based on routine clinical care. Recommended visits and assessments should be planned 2, 4, 12, and 24 weeks following initiation of TMC207 in combination with the BR and 4 weeks (Week 28) and every 24 weeks (Weeks 48, 72, 96, and 120) after completion of TMC207 intake during the 96-week follow-up period. If needed, extra visits and assessments can be planned at the discretion of the investigator in order to best manage the patient's TB treatment. Patients who are taking clofazimine with TMC207 will require electrocardiogram (ECG) monitoring at mandatory protocol-specified visits. Serum chemistry (electrolytes) assessment will be performed at every visit in which an ECG is performed. After their last intake of TMC207, all patients will continue to take their BR under the supervision of their treating physician or local health center/hospital in accordance with NTP guidelines and local multi-drug resistant (MDR) TB treatment practice (i.e., treatment may be extended for reasons of complicated lung disease, etc.). Patients will be followed up for 96 weeks (2 years) after their last dose of TMC207 to evaluate the microbiological effect (verification of microbiological status \[measured locally as per local standard of care; eg, smear, culture, DST\] is recommended to be performed every 24 weeks) that TMC207 has provided these patients, as well as to monitor the safety and tolerability of TMC207. Patients who withdraw early, unless due to withdrawal of informed consent, will be followed for survival/clinical outcome (approximately every 6 months) until the early access study comes to an end in the patients' corresponding country. Patients can enter the study until TMC207 will be commercially available in the patient's country or can be accessed from another source or until discontinuation of the development program of TMC207.

Conditions

Interventions

Eligibility

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