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Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine for Treatment of Patients With MDR-TB (DRAMATIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03828201
Recruitment Status : Withdrawn (The study could not be conducted since funding was not obtained)
First Posted : February 4, 2019
Last Update Posted : May 8, 2019
Sponsor:
Collaborators:
United States Department of Defense
Novartis Pharmaceuticals
Pfizer
Otsuka Pharmaceutical Co., Ltd.
Information provided by (Responsible Party):
Charles R Horsburgh, Boston University

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 558,000 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.

The investigators propose to randomize participants with MDR-TB to 16 or 24 weeks of treatment with a 5-drug oral experimental regimen or to the standard World Health Organization (WHO) 9-11-month regimen (the "control" regimen). The primary objective is to assess the non-inferiority of the 24-week experimental regimen. In addition, the study also aims to examine the non-inferiority of an even shorter (16-week) regimen. The proposed investigational regimen combines two new drugs, bedaquiline (BDQ) and delamanid (DLM), with three anti-TB agents of known potency, linezolid (LZD), levofloxacin (LFX), and clofazimine (CF), to provide a shorter, better-tolerated and more effective MDR-TB treatment regimen for persons with fluoroquinolone-susceptible MDR-TB. This regimen can be expected to be effective for the vast majority of MDR-TB patients throughout the world.


Condition or disease Intervention/treatment Phase
Tuberculosis, Multidrug-Resistant Drug: Delamanid Drug: Levofloxacin Drug: Bedaquiline Drug: Clofazimine Drug: Linezolid Combination Product: WHO approved MDR-TB treatment regimens Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective, Randomized, Partially Blinded, Phase 3 Study of the Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine for Treatment of Patients With MDR-TB
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : January 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: Investigational: DRAMATIC-16 weeks
delamanid 200 mg orally, by mouth (PO) once a day (QD), 16 weeks levofloxacin 1000 mg PO QD, 16 weeks clofazimine 100 mg PO QD, 16 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder, 16 weeks linezolid 1200 mg PO QD, 16 weeks
Drug: Delamanid

Frequency: daily Route of administration: oral

Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Other Name: Deltyba

Drug: Levofloxacin

Frequency: daily Route of administration: oral

Levofloxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

Other Name: Levaquin

Drug: Bedaquiline

Frequency: daily Route of administration: oral

Bedaquiline is indicated for use as part of an appropriate combination regimen for pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.

Other Name: Sirturo

Drug: Clofazimine

Frequency: daily Route of administration: oral

Clofazimine has shown activity against multidrug-resistant tuberculosis (MDR-TB) and is now recommended by the World Health Organization (WHO) to treat drug resistant tuberculosis as a "Group B" drug. It is thought that clofazimine acts by inhibiting the formation of matrixes within the DNA and thus delaying the growth of the bacterium. Clofazimine first received FDA approval in 1986, although its use in the treatment of MDR-TB has not been approved by any stringent regulatory authorities and it is therefore used "off-label" for this function.

Other Name: Lamprene

Drug: Linezolid

Frequency: daily Route of administration: oral

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

Other Name: Zyvox

Experimental: Investigational: DRAMATIC-24 weeks
delamanid 200 mg PO QD, 24weeks levofloxacin 1000 mg PO QD, 24 weeks clofazimine 100 mg PO QD, 24 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder, 24 weeks linezolid 1200 mg PO QD, 24 weeks
Drug: Delamanid

Frequency: daily Route of administration: oral

Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Other Name: Deltyba

Drug: Levofloxacin

Frequency: daily Route of administration: oral

Levofloxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

Other Name: Levaquin

Drug: Bedaquiline

Frequency: daily Route of administration: oral

Bedaquiline is indicated for use as part of an appropriate combination regimen for pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.

Other Name: Sirturo

Drug: Clofazimine

Frequency: daily Route of administration: oral

Clofazimine has shown activity against multidrug-resistant tuberculosis (MDR-TB) and is now recommended by the World Health Organization (WHO) to treat drug resistant tuberculosis as a "Group B" drug. It is thought that clofazimine acts by inhibiting the formation of matrixes within the DNA and thus delaying the growth of the bacterium. Clofazimine first received FDA approval in 1986, although its use in the treatment of MDR-TB has not been approved by any stringent regulatory authorities and it is therefore used "off-label" for this function.

Other Name: Lamprene

Drug: Linezolid

Frequency: daily Route of administration: oral

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

Other Name: Zyvox

Active Comparator: Control: WHO 9-11 mo
World Health Organization (WHO) approved MDR-TB treatment regimens(1)
Combination Product: WHO approved MDR-TB treatment regimens

In patients with Rifampicin-resistant (RR-TB) or MDR-TB who were not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of the longer regimens.

In patients with RR-TB or MDR-TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines - one chosen from Group A, one from Group B, and at least two from Group C1 (conditional recommendation, very low certainty in the evidence). If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five.

In patients with RR-TB or MDR-TB, it is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (1).

Other Name: WHO 9-11 month regimen




Primary Outcome Measures :
  1. Treatment Efficacy - Frequency of "successful" participant outcomes [ Time Frame: Week 78 ]

    A participant's outcome will be classified as successful if, at 78 weeks after initiation of treatment, they have a "negative" sputum culture and were not previously classified as unsuccessful.

    A participant's outcome will be classified as unsuccessful if any of the following occur prior to week 78: Addition or replacement of 2 or more anti-tuberculosis (TB) drugs from the assigned regimen or undergoing surgery for multidrug-resistant TB (MDR-TB), loss to follow-up, extended treatment, and death.


  2. Treatment Safety - Frequency of participants with grade 3,4, or 5 adverse events [ Time Frame: Week 78 ]
    The primary outcome for safety are Grade 3,4, or 5 adverse events


Secondary Outcome Measures :
  1. Frequency of QTc prolongation [ Time Frame: Week 8 ]
    At the beginning of the study, a QT safety run-in substudy will be performed, comprising 36 adult patients (12 in each arm). We aim to characterize the frequency of the corrected QT interval (QTc) prolongation associated with the study regimen.

  2. Magnitude of QTc prolongation [ Time Frame: Week 8 ]
    At the beginning of the study, a QT safety run-in substudy will be performed, comprising 36 adult patients (12 in each arm). We aim to characterize the magnitude (in msec) of the corrected QT interval (QTc) prolongation associated with the study regimen.

  3. Time course of QTc prolongation [ Time Frame: Week 8 ]
    At the beginning of the study, a QT safety run-in substudy will be performed, comprising 36 adult patients (12 in each arm). We aim to characterize the time course of the corrected QT interval (QTc) prolongation associated with the study regimen.

  4. Treatment safety and tolerability - Frequency of adverse events [ Time Frame: Week 78 ]

    Describe the relationship between duration of the oral regimen and safety and tolerability of the regimen.

    A participant's outcome will be classified as successful if, at 78 weeks after initiation of treatment, they have a "negative" sputum culture and were not previously classified as unsuccessful. A participant's outcome will be classified as unsuccessful if any of the following occur prior to week 78: Addition or replacement of 2 or more anti-TB drugs from the assigned regimen or undergoing surgery for MDR-TB, loss to follow-up, extended treatment, and death.


  5. Duration of the experimental regimen [ Time Frame: Week 78 ]
    Estimate the minimum duration of the experimental regimen that is non-inferior to the WHO standard 9-month regimen.

  6. Treatment success in subpopulations - Frequency of "successful" participant outcomes [ Time Frame: Week 78 ]
    Describe the relationship between the duration of the oral regimen and the proportion of successful outcomes in the following subpopulations: HIV-infected persons, persons with extensive pulmonary disease, persons with greater baseline bacterial burden in sputum.

  7. Survival - Frequency of participants who survive [ Time Frame: Week 132 ]
    Evaluate survival at 132 weeks post randomization.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females age ≥12 years. If ≥18 years of age, is able to provide informed consent; if <18 years of age, is able to provide informed assent and has a parent or guardian who is able to provide informed consent on the participant's behalf.
  2. Has pulmonary tuberculosis (TB) based on investigator assessment of all available information (e.g., chest x-ray, sputum smear, culture, molecular testing).
  3. Has a sputum sample that is positive for M. tuberculosis (MTB) that is rifamycin-resistant and fluoroquinolone-susceptible by molecular assay.
  4. Is human immunodeficiency virus (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. Women with 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.

Exclusion Criteria:

  1. Current MTB isolate is known at screening to be quinolone-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 prior treatment with delamanid or linezolid for TB
  7. Has at screening received ≥14 days of second-line anti-TB drugs
  8. Has at screening a Karnofsky score of ≤40 or, in the opinion of the Investigator, is unlikely to survive 78 weeks.
  9. Has at screening > 40 decibel (dB) hearing at 4000 Hz in either ear
  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 Alanine Aminotransferase (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 indeterminant serum pregnancy test
  11. For women of childbearing potential, has a positive or indeterminant urine pregnancy test on the day of randomization.
  12. Has at screening a mean QT interval with Fridericia's correction (QTcF) >450 msec based on three electrocardiograms (ECGs).
  13. At screening requires ongoing use of prohibited drugs indicated in section 4.2
  14. At screening, has weight less than 33 Kg.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03828201


Sponsors and Collaborators
Boston University
United States Department of Defense
Novartis Pharmaceuticals
Pfizer
Otsuka Pharmaceutical Co., Ltd.
Investigators
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Principal Investigator: Charles Horsburgh, MD Boston University School of Public Health, Center for Global Health
Publications:
1. World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis: 2016 update. Geneva, Switzerland. 2016.
2. World Health Organization. Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). Geneva, Switzerland. 2018.
3. World Health Organization. Global tuberculosis report. 2018.
4. International Union Against Tuberculosis and Lung Disease. STREAM clinical trial results provide vital insight into nine-month treatment regimen for multidrug-resistant tuberculosis. 2017. Available from: http://guadalajara.worldlunghealth.org/media/conference-news/updates/stream-clinical-trial-results-provide-vital-insight-into-nine-month-treatment-regimen-for-multidrug-resistant-tuberculosis.

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Responsible Party: Charles R Horsburgh, Professor of Epidemiology, Boston University, Boston University
ClinicalTrials.gov Identifier: NCT03828201    
Other Study ID Numbers: H38212
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: May 8, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Charles R Horsburgh, Boston University:
WHO 9-11-month regimen for MDR-TB
bedaquiline (BDQ)
delamanid (DLM)
linezolid (LZD)
levofloxacin (LFX)
clofazimine (CF)
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Levofloxacin
Ofloxacin
Linezolid
Bedaquiline
Clofazimine
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Anti-Bacterial Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Protein Synthesis Inhibitors
Antitubercular Agents
Anti-Inflammatory Agents
Leprostatic Agents