Trial record 6 of 33 for:
A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis
This study is currently recruiting participants.
Verified August 2016 by Global Alliance for TB Drug Development
Information provided by (Responsible Party):
Global Alliance for TB Drug Development
First received: January 6, 2015
Last updated: February 28, 2017
Last verified: August 2016
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).
||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
||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).
Primary Outcome Measures:
- Incidence of bacteriologic failure or relapse or clinical failure through follow up until 24 months after the end of treatment. [ Time Frame: 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 ]
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.
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 21 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.
Secondary Outcome Measures:
- Time to sputum culture conversion to negative status through the treatment period. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: Weeks 2, 8 and 16 ]
- Time to sputum culture positivity [ Time Frame: 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 ]
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.
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||October 2018 (Final data collection date for primary outcome measure)
Experimental: Bedaquiline + PA-824 + Linezolid
bedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 600mg twice daily.
Scored 600mg tablets
|Ages Eligible for Study:
||14 Years and older (Child, Adult, Senior)
|Sexes Eligible for Study:
|Accepts Healthy Volunteers:
- Provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian).
- Body weight of ≥30 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]).
- Male or female, aged 14 years or above.
Subjects with one of the following pulmonary TB conditions:
- XDR-TB documented by culture positive (for M.tb.) results (with resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable within 3 months prior to screening);
- MDR-TB documented by culture positive results (for M.tb.) within 3 months prior to screening with documented non-response to treatment with the best available regimen for 6 months or more prior to enrollment who in the opinion of the Investigator have been adherent to treatment and will be adherent to study regimen;
- MDR-TB documented by culture positive (for M.tb.) results within 3 months prior to 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:
- 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.
- 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.
- 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.
- 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. In the case of resistance or intolerance to the above two regimens, a triple nucleosidase reverse trascriptase inhibitors (NRTI) based regimen consisting of zidovudine, lamivudine and abacavir may be used with caution;
iv. 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 enrollment. 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 ms.
- Females who have a positive pregnancy test at Screening or already known to be pregnant, breast-feeding, 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.
- Concommitant 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 myelosuppresion.
Subjects may have previously been treated for DS/MDR-TB provided that treatment is/was discontinued at least 3 days prior to treatment assignment.
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 of < 8.0 g/dL;
- Platelet count < 80,000/mm3;
- Absolute neutrophil count (ANC) < 1000/ mm3;
- aspartate aminotransferase (AST) ≥5.0 x ULN. Subjects with AST > 3.0 x ULN must be discussed with the sponsor medical monitor before enrolment;
- alanine aminotransferase (ALT) ≥5.0 x ULN. Subjects with ALT > 3.0 x ULN must be discussed with the sponsor medical monitor before enrolment;
- total bilirubin grade 3 or greater (≥2.0 x ULN, or ≥1.50 x ULN when accompanied by any increase in other liver function test);
- Serum creatinine level greater than 2 times upper limit of normal.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02333799
|Task Applied Science - Brooklyn Chest Hospital
|Ysterplaat, Cape Town, South Africa, 7405 |
|Contact: Andreas Diacon firstname.lastname@example.org |
|Principal Investigator: Andreas Diacon |
|Sizwe Tropical Disease Hospital
|Sandringham, Johannesburg, South Africa, 2131 |
|Contact: Francesca Conradie 27 (0) 11 531 4347 email@example.com |
|Principal Investigator: Francesca Conradie |
|THINK: Tuberculosis & HIV Investigative Network of KwaZulu-Natal (Durban)
|Pietermaritzburg, Kwazulu-Natal, South Africa, 3200 |
|Contact: Suzanne Staples 27 (0) 31 303 1120 firstname.lastname@example.org |
|Principal Investigator: Suzanne Staples |
Global Alliance for TB Drug Development
||Global Alliance for TB Drug Development
||CHRU Themba Lethu Clinic - Helen Joseph Hospital
||Global Alliance for TB Drug Development
History of Changes
|Other Study ID Numbers:
|Study First Received:
||January 6, 2015
||February 28, 2017
Keywords provided by Global Alliance for TB Drug Development:
Extensively drug resistant
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on September 19, 2017
Extensively Drug-Resistant Tuberculosis
Gram-Positive Bacterial Infections
Respiratory Tract Diseases
Respiratory Tract Infections
Protein Synthesis Inhibitors
Molecular Mechanisms of Pharmacological Action