Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB
NCT03828201
ABOUT THIS STUDY
FOR MORE INFORMATION
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1. Males and females age ≥12 years. Prior to study procedures, if ≥18 years of age, provides informed consent; if <18 years of age, child provides informed assent and has a parent or guardian who provides informed consent on the participant's behalf.
2. Has pulmonary TB based on investigator assessment of all available information (e.g., chest radiograph, sputum smear, culture, molecular testing).
3. Has a sputum sample that is positive for M. tuberculosis that is rifamycin-resistant and fluoroquinolone-susceptible by molecular assay.
4. Is HIV seropositive or seronegative; HIV serostatus must be assessed at screening if either (a) HIV serostatus is unknown, or (b) the last documented negative HIV test was more than two (2) months prior to screening.
5. Willing to attend scheduled follow-up visits and undergo study assessments.
6. Participants of child-bearing potential must agree either (a) to practice an adequate birth control (defined as one of the following oral contraceptives, intrauterine devices, contraceptive implants under the skin, contraceptive rings or patches or injections, diaphragms with spermicide or condoms with foam) or (b) to abstain from heterosexual intercourse during study regimen.
1. Current MTB isolate is known at screening to be fluoroquinolone-resistant.
2. History of allergy (hypersensitivity) or intolerability to one or more agents in the
investigational regimens (i.e., Arms 1 and 2)
3. History of serotonin syndrome
4. History of symptomatic ventricular arrhythmia or is taking anti-arrhythmic agents
5. History of optic neuropathy or peripheral neuropathy
6. History of Ehlers-Danlos Syndrome, Marfan Syndrome or aortic aneurism
7. History of prior treatment with delamanid or linezolid for TB for greater than one
month.
8. Has at screening received ≥14 days of second-line anti-TB drugs during current TB
episode
9. Has at screening a Karnofsky score of ≤40 or, in the opinion of the Investigator, is
unlikely to survive 76 weeks.
10. Has at screening laboratory results that meet one or more of the following criteria:
- Hemoglobin concentration <7.0 g/dL (<70 g/L)
- Platelet count of <80,000/mm3
- Absolute neutrophil count (ANC) <2000/ mm3
- Serum creatinine >2.0 mg/dL (>177 µmol/L)
- Serum ALT >3x upper limit of normal (ULN)
- Total bilirubin >3x upper limit of normal (ULN)
- Serum albumin <2.8 g/dL (<28 g/L)
- For women of childbearing potential, a positive or indeterminate serum pregnancy
test
11. For women of childbearing potential, has a positive or indeterminate urine pregnancy
test on the day of randomization.
12. Has at screening a mean QTcF >450 msec based on three ECGs.
13. At screening requires ongoing use of prohibited drugs indicated in section 4.2
14. At screening, has weight less than 33 Kg.
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Descriptive Information | |||||||||
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Brief Title ICMJE | Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB | ||||||||
Official Title ICMJE | Prospective, Randomized, Partially Blinded, Phase 2 Study of the Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine for Treatment of Patients With MDR-TB | ||||||||
Brief Summary | Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis (TB) that is resistant to at least isoniazid and rifampicin, the two most important anti-TB drugs. It occurs in 3.6% of newly diagnosed TB patients in the world and 17% of patients who have been previously treated. In 2017, approximately 600,000 people were estimated to have acquired MDR-TB. However, only 25% of persons with MDR-TB were diagnosed and started on treatment, reflecting inadequate diagnostic capacity and lack of TB treatment capacity. In this multicenter, randomized, partially blinded, four-arm, phase 2 study, the investigators will examine the efficacy and safety of an all-oral regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine given for 16, 24, 32 or 40 weeks | ||||||||
Detailed Description | Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis that is resistant to at least isoniazid and rifampicin, the two most important drugs in treating TB. In 2017, approximately 558,000 new people were estimated to have developed MDR-TB, and 8.5% of the cases had extensively drug-resistant tuberculosis (XDR-TB).(1) Current WHO-endorsed MDR-TB treatment regimens take 9-20 months to complete and are associated with substantial toxicity, including deafness from injectable agents, hepatitis from pyrazinamide and severe neuropathy from linezolid. Given the long duration and toxicities of MDR-TB regimens, it is perhaps not surprising that WHO reports that only 25% of patients with MDR-TB are enrolled into WHO-endorsed treatment regimens. Thus, there is an urgent need for shorter, less toxic treatments for MDR-TB. This proposal will determine the efficacy, safety, tolerability and optimal duration of a novel, all oral MDR-TB treatment regimen while addressing three major challenges with innovations that have the potential to transform future trials. The proposed DRAMATIC (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical) Trial is a multicenter, randomized, partially blinded, four-arm, phase 2 trial that will examine an injectable- and pyrazinamide-sparing regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine. The DRAMATIC regimen limits the administration of linezolid to the initial 8 weeks of treatment, the window before linezolid-related neuropathy occurs. Animal and human studies provide evidence for the potential efficacy of this 5-drug regimen, but the optimal duration of treatment remains uncertain.(2-4) Primary Objectives:
Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability of TB control programs to treat the growing number of patients. The DRAMATIC Trial will employ an innovative and efficient new design to establish a robust, nontoxic MDR-TB treatment regimen and identify the minimal duration for which it needs to be administered. These results will speed the process of moving forward to a confirmatory phase 3 clinical trial and increase the likelihood that such a trial is successful. | ||||||||
Study Type ICMJE | Interventional | ||||||||
Study Phase ICMJE | Phase 2 | ||||||||
Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment | ||||||||
Condition ICMJE | Tuberculosis, Multidrug-Resistant | ||||||||
Intervention ICMJE |
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Study Arms ICMJE |
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Publications * | Not Provided | ||||||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. | |||||||||
Recruitment Information | |||||||||
Recruitment Status ICMJE | Not yet recruiting | ||||||||
Estimated Enrollment ICMJE | 220 | ||||||||
Original Estimated Enrollment ICMJE | 465 | ||||||||
Estimated Study Completion Date ICMJE | July 2025 | ||||||||
Estimated Primary Completion Date | July 2025 (Final data collection date for primary outcome measure) | ||||||||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 12 Years and older (Child, Adult, Older Adult) | ||||||||
Accepts Healthy Volunteers ICMJE | No | ||||||||
Contacts ICMJE |
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Listed Location Countries ICMJE | Philippines, Vietnam | ||||||||
Removed Location Countries | |||||||||
Administrative Information | |||||||||
NCT Number ICMJE | NCT03828201 | ||||||||
Other Study ID Numbers ICMJE | H39017 U01AI152980 ( U.S. NIH Grant/Contract ) | ||||||||
Has Data Monitoring Committee | Yes | ||||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Responsible Party | Boston University | ||||||||
Study Sponsor ICMJE | Boston University | ||||||||
Collaborators ICMJE |
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Investigators ICMJE |
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PRS Account | Boston University | ||||||||
Verification Date | November 2020 | ||||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |