Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB

NCT03828201 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: H39017U01AI152980
• Study Type: interventional
• Target: 271
• Locations: 2 countries
• Sites: 2

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

Conditions

Tuberculosis, Multidrug-Resistant

Keywords

bedaquiline (BDQ); delamanid (DLM); linezolid (LZD); levofloxacin (LFX); clofazimine (CF)

Outcome Measures

Primary Outcomes (2)

• Treatment Efficacy - Frequency of "successful treatment" outcomes

  A participant's outcome will be classified as successful if, at 76 weeks after initiation of treatment, they have a "negative" sputum culture and were not previously classified as unsuccessful; if the participant is unable to produce sputum at that time, the outcome will be classified as successful if they had a negative culture result at the last visit at which they had a sputum culture result. A participant's outcome will be classified as unsuccessful if any of the following occur prior to week 76: Addition or replacement of 2 or more anti-tuberculosis (TB) drugs from the assigned regimen, the participant has a positive culture for M. tuberculosis and that isolate is not demonstrated to be genetically different from the initial isolate, undergoing surgery for multidrug-resistant TB (MDR-TB), lost to follow-up, surgery for MDR-TB, extended treatment, and death.

  Week 76

• Treatment Safety - Frequency of participants with grade 3, 4, or 5 adverse events

  The primary outcome for safety are Grade 3, 4, or 5 adverse events

  44 weeks

Secondary Outcomes (1)

• Efficacy outcome- Frequency of participants who survive

  Week 132

Study Arms (4)

Investigational: DRAMATIC-16 weeks

EXPERIMENTAL

delamanid 300 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 linezolid 600 mg PO QD, Initial 16 weeks only

Drug: Delamanid; Drug: Levofloxacin; Drug: Bedaquiline; Drug: Clofazimine; Drug: Linezolid

Investigational: DRAMATIC-24 weeks

EXPERIMENTAL

delamanid 300 mg orally, by mouth (PO) once a day (QD), 24 weeks 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 linezolid 600 mg PO QD, Initial 16 weeks only

Drug: Delamanid; Drug: Levofloxacin; Drug: Bedaquiline; Drug: Clofazimine; Drug: Linezolid

Investigational: DRAMATIC-32 weeks

EXPERIMENTAL

delamanid 300 mg orally, by mouth (PO) once a day (QD), 32 weeks levofloxacin 1000 mg PO QD, 32 weeks clofazimine 100 mg PO QD, 32 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 600 mg PO QD, Initial 16 weeks only

Drug: Delamanid; Drug: Levofloxacin; Drug: Bedaquiline; Drug: Clofazimine; Drug: Linezolid

Investigational: DRAMATIC-40 weeks

EXPERIMENTAL

delamanid 300 mg orally, by mouth (PO) once a day (QD), 40 weeks levofloxacin 1000 mg PO QD, 40 weeks clofazimine 100 mg PO QD, 40 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 600 mg PO QD, Initial 16 weeks only

Drug: Delamanid; Drug: Levofloxacin; Drug: Bedaquiline; Drug: Clofazimine; Drug: Linezolid

Interventions

Delamanid DRUG

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.

Also known as: Deltyba

Investigational: DRAMATIC-16 weeks; Investigational: DRAMATIC-24 weeks; Investigational: DRAMATIC-32 weeks; Investigational: DRAMATIC-40 weeks

Levofloxacin DRUG

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.

Also known as: Levaquin

Investigational: DRAMATIC-16 weeks; Investigational: DRAMATIC-24 weeks; Investigational: DRAMATIC-32 weeks; Investigational: DRAMATIC-40 weeks

Bedaquiline DRUG

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.

Also known as: Sirturo

Investigational: DRAMATIC-16 weeks; Investigational: DRAMATIC-24 weeks; Investigational: DRAMATIC-32 weeks; Investigational: DRAMATIC-40 weeks

Clofazimine DRUG

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.

Also known as: Lamprene

Investigational: DRAMATIC-16 weeks; Investigational: DRAMATIC-24 weeks; Investigational: DRAMATIC-32 weeks; Investigational: DRAMATIC-40 weeks

Linezolid DRUG

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.

Also known as: Zyvox

Investigational: DRAMATIC-16 weeks; Investigational: DRAMATIC-24 weeks; Investigational: DRAMATIC-32 weeks; Investigational: DRAMATIC-40 weeks

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Has pulmonary TB based on investigator assessment of all available information (e.g., chest radiograph, sputum smear, culture, molecular testing).
• Has a sputum sample that is positive for M. tuberculosis that is rifamycin-resistant and fluoroquinolone-susceptible by molecular assay.
• 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.
• Willing to attend scheduled follow-up visits and undergo study assessments.
• 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.

You may not qualify if:

• Current MTB isolate is known at screening to be fluoroquinolone-resistant.
• History of allergy (hypersensitivity) or intolerability to one or more agents in the investigational regimens (i.e., Arms 1 and 2)
• History of serotonin syndrome
• History of symptomatic ventricular arrhythmia or is taking anti-arrhythmic agents
• History of optic neuropathy or peripheral neuropathy
• History of Ehlers-Danlos Syndrome, Marfan Syndrome or aortic aneurism
• History of prior treatment with delamanid or linezolid for TB for greater than one month.
• Has at screening received ≥14 days of second-line anti-TB drugs during current TB episode
• Has at screening a Karnofsky score of ≤40 or, in the opinion of the Investigator, is unlikely to survive 76 weeks.
• Has at screening laboratory results that meet one or more of the following criteria:
• Hemoglobin concentration 8.0 g/dL (\<80 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)

Sponsors & Collaborators

• Boston University: lead
• Novartis Pharmaceuticals: collaborator
• Pfizer: collaborator
• Otsuka Pharmaceutical Co., Ltd.: collaborator
• University of California, San Francisco: collaborator
• Westat: collaborator
• University of Colorado, Denver: collaborator
• Harvard Medical School (HMS and HSDM): collaborator
• National Lung Hospital, Vietnam: collaborator
• De La Salle Health Sciences Institute, Philippines: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

De La Salle Health Sciences Institute

Dasmariñas, 4114, Philippines

Location

National Lung Hospital

Hanoi, Vietnam

Location

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant

Interventions

OPC-67683; Levofloxacin; bedaquiline; Clofazimine; Linezolid

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Ofloxacin; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Phenazines; Heterocyclic Compounds, 3-Ring; Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Charles Horsburgh, MD

  Boston University

  PRINCIPAL INVESTIGATOR

• Payam Nahid, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Epidemiology, Boston University

Study Record Dates

• First Submitted: January 29, 2019
• First Posted: February 4, 2019
• Study Start: June 7, 2022
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027
• Last Updated: April 14, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

VN (1); PH (1)