A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety, tolerability and pharmacokinetics of bedaquiline plus PA-824 plus linezolid after 6 months of treatment (option for 9 months for subjects who remain culture positive at month 4) in Subjects with either pulmonary extensively drug resistant tuberculosis (XDR-TB), treatment intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB).

Official Title
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A Phase 3 Open-label Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB) or Treatment Intolerant / Non-responsive Multi-drug Resistant Tuberculosis (MDR-TB).

Conditions
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Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: Bedaquiline
* Drug: PA-824
* Drug: Linezolid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian). Body weight of ≥35 kg (in light clothing and no shoes). Willingness and ability to attend scheduled follow-up visits and undergo study assessments Provide consent to HIV testing (if an HIV test was performed within 1 month prior to trial start, it should not be repeated as long as documentation can be provided [ELISA and/or Western Blot]. If HIV status is a confirmed known positive, repeated HIV test is not needed provided documentation is available. Male or female, aged 14 years or above. Subjects with one of the following pulmonary TB conditions: a. XDR-TB with i. documented culture positive (for M.tb.) results within 3 months prior to screening or M.tb. confirmed in sputum based on molecular test within 3 months prior to or at screening; ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable historically at any time or at screening; b. MDR-TB documented by culture positive results (for M.tb.) within 3 months prior to or at screening with documented non-response to treatment with the best available regimen for 6 months or more prior to enrolment who in the opinion of the Investigator have been adherent to treatment and will be adherent to study regimen; c. MDR-TB documented by culture positive (for M.tb.) results within 3 months prior to or at screening who are unable to continue second line drug regimen due to a documented intolerance to: i. PAS, ethionamide, aminoglycosides or fluoroquinolones; ii. Current treatment not listed above that renders subject eligible for the study in the Investigator's opinion. Chest X-Ray picture (taken within a year prior to screening) consistent with pulmonary TB in the opinion of the Investigator. Be of non-childbearing potential or using effective methods of birth control, as defined below: Non-childbearing potential: Subject - not heterosexually active or practices sexual abstinence; or Female Subject/sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or Male Subject/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to Screening. Effective birth control methods: A double contraceptive method should be used as follows: Double barrier method which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); or Barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female Subject/partner; and are willing to continue practicing birth control methods throughout treatment and for 6 months (both male and female Subjects) after the last dose of study medication or discontinuation from study medication in case of premature discontinuation. Note: Hormone based contraception alone may not be reliable when taking investigational medicinal products; therefore, hormone based contraceptives alone cannot be used by female Subjects or female partners of male Subjects to prevent pregnancy. Exclusion Criteria Medical History Any condition in the Investigator's opinion (i.e., an unstable disease such as uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended treatment), where participation in the trial would compromise the well-being of Subject or prevent, limit or confound protocol specified assessments. Abuse of alcohol or illegal drugs, that in the opinion of the Investigator would compromise the Subjects' safety or ability to follow through with all protocol-specified visits and evaluations. In the judgment of the Investigator, the patient is not expected to survive for more than 12 weeks. Karnofsky score < 50 within 30 days prior to entry. Body Mass index (BMI) < 17 kg/m² History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances. HIV infected Subjects having a CD4+ count ≤ 50 cells/μL; For HIV infected Subjects having a CD4+ count >50 cells/μL; a. Currently treated with or will need to initiate antiretroviral therapy (ART) which is not compatible with the allowed ARTs and is not considered an appropriate candidate for switching to a regimen of ARVs which is allowed. Examples of allowed treatment include but are not limited to the following. If there are any questions, discuss with the Sponsor Medical Monitor for confirmation of appropriate ARV regimen. i. Nevirapine based regimen consisting of nevirapine in combination with any NRTIs; ii. Lopinavir/ritonavir (Aluvia™) based regimen consisting of lopinavir/ritonavir (Aluvia™) in combination with any NRTIs; iii. The combination of tenofovir/lamivudine/abacavir should be considered in patients with normal renal function to address myelosuppression cross toxicity of idovudine and linezolid; iv. An alternate regimen that may be considered if the above are not appropriate is a triple nucleosidase reverse transcriptase inhibitors (NRTI) based regimen consisting of zidovudine, lamivudine and abacavir may be used with caution. Regimens including zidovudine should be used with special caution as zivovudine and linezolid may both cause peripheral nerve toxicity; v. Raltegravir in combination with nucleoside reverse transcriptase inhibitors (NRTIs). b. Cannot ensure a 2 week interval between commencing IMP and the start of ART, if not already on ARTs. Having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational study that includes treatment with medicinal agents. Subjects who are participating in observational studies or who are in a follow up period of a trial that included drug therapy may be considered for inclusion. Significant cardiac arrhythmia requiring medication. Subjects with the following at Screening: QTcF interval on ECG >500 msec. Subjects with QTcF > 450 must be discussed with the sponsor medical monitor before enrolment. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); Clinically significant ventricular arrhythmias; Subjects with other cardiac abnormalities that may place them at risk of arrhythmias must be discussed with the sponsor medical monitor before enrolment. Such abnormalities include: Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome); Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; Evidence of second or third degree heart block; Intraventricular conduction delay with QRS duration more than 120 msec. Females who have a positive pregnancy test at Screening or already known to be pregnant, breastfeeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, subjects with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of treatment assignment. Concomitant use of serotonergic antidepressants or prior use within 3 days of treatment assignment if Investigator foresees potential risks for serotonin syndrome when combined with linezolid. Concomitant use of any drug known to prolong QTc interval (including, but not limited to, amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, fluoroquinolones, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine). Concomitant use of any drug known to induce myelosuppression. Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes(including but not limited to quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may be made for subjects that have received 3 days or less of one of these drugs or substances, if there has been a wash-out period before administration of IMP equivalent to at least 5 half-lives of that drug or substance. Subjects may have previously been treated for DS/MDR-TB (with specific excepetions for Bedaquiline and/or linezolid as noted below) provided that treatment is/was discontinued at least 3 days prior to treatment assignment. Subjects should not receive more than 2 weeks of bedaquiline or linezolid prior to enrolment/first dose of IMP. Based on Laboratory Abnormalities Subjects with the following toxicities at Screening (labs may be repeated) as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007): serum potassium less than the lower limit of normal for the laboratory; Hemoglobin level grade 2 or greater (< 8.0 g/dL); Platelets grade 2 or greater(<75,000/mm3); Absolute neutrophil count (ANC) < 1000/ mm3; Aspartate aminotransferase (AST) Grade 3 or greater (> 3.0 x ULN) to be excluded; Greater than ULN must be discussed with and approved by the sponsor Medical Monitor Alanine aminotransferase Grade 3 or greater (> 3.0 x ULN) to be excluded greater than ULN must be discussed with and approved by the sponsor medical monitor ; Total bilirubin: Grade 3 or greater (≥2.0 x ULN), or if ≥1.5 up to 2.0 x ULN when accompanied by an increase in other liver function test (ALT, AST, Alk Phos or GGT); 1-1.5 x ULN must be discussed with and approved by the sponsor Medical Monitor Direct bilirubin: Greater than ULN to be excluded Serum creatinine level greater than 2 times upper limit of normal Albumin <32 g/L

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bedaquiline + PA-824 + Linezolid<br>bedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 1200mg once daily . | Drug: Bedaquiline<br>* 100mg tablets<br>* Other names: TMC-207;Drug: PA-824<br>* 200mg tablets<br>* Other names: pretomanid;Drug: Linezolid<br>* Scored 600mg tablets<br>* Other names: Lin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of bacteriologic failure or relapse or clinical failure through follow up until 6 months after the end of treatment. | Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative. Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline. Clinical failure: A change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death. Note: Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart. Subjects who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit. | Treatment Period: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39 Follow Up: Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to sputum culture conversion to negative status through the treatment period. |  | Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 | 
| Proportion of subjects with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 26 or 39 weeks. |  | Week 4, 6, 8, 12, 16, 26, 39 | 
| Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, and seriousness, leading to TB related or non-TB related death. |  | Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39, Follow-up Month 3, 6, 9, 12, 15, 18, 21, 24 | 
| All Subjects- Pre-dose sampling at weeks 2, 8 and 16 to measure Ctrough levels of bedaquiline, bedaquiline metabolite M2, Linezolid and PA-824. |  | Weeks 2, 8 and 16 | 
| Time to sputum culture positivity | If liquid culture in the MGIT platform is used, the rate of change in time to sputum culture positivity (TTP) over time in the Mycobacterial Growth Indicator Tube (MGIT) system in sputum, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. | Treatment Period: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39 Follow Up: Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, MDR-TB, XDR-TB, Multi-drug resistant, Extensively drug resistant, Bedaquiline, PA-824, Linezolid, TB, Pretomanid, TMC-207, NiX-TB