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

Primary Purpose

Tuberculosis, Multidrug-Resistant

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Delamanid
Levofloxacin
Bedaquiline
Clofazimine
Linezolid
Sponsored by
Boston University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis, Multidrug-Resistant focused on measuring bedaquiline (BDQ), delamanid (DLM), linezolid (LZD), levofloxacin (LFX), clofazimine (CF)

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  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.

Exclusion Criteria:

  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.

Sites / Locations

  • De La Salle Health Sciences InstituteRecruiting
  • National Lung Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Investigational: DRAMATIC-16 weeks

Investigational: DRAMATIC-24 weeks

Investigational: DRAMATIC-32 weeks

Investigational: DRAMATIC-40 weeks

Arm Description

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 1200 mg PO QD, Initial 8 weeks only

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 1200 mg PO QD, Initial 8 weeks only

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 1200 mg PO QD, Initial 8 weeks only

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 1200 mg PO QD, Initial 8 weeks only

Outcomes

Primary Outcome Measures

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.
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

Secondary Outcome Measures

Efficacy outcome- Frequency of participants who survive
Evaluate survival at 132 weeks post randomization.

Full Information

First Posted
January 29, 2019
Last Updated
June 9, 2023
Sponsor
Boston University
Collaborators
Novartis Pharmaceuticals, Pfizer, Otsuka Pharmaceutical Co., Ltd., University of California, San Francisco, Westat, National Institute of Allergy and Infectious Diseases (NIAID), University of Colorado, Denver, Harvard Medical School (HMS and HSDM), National Lung Hospital, Vietnam, De La Salle Health Sciences Institute, Philippines
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1. Study Identification

Unique Protocol Identification Number
NCT03828201
Brief Title
Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB
Acronym
DRAMATIC
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 7, 2022 (Actual)
Primary Completion Date
July 2025 (Anticipated)
Study Completion Date
July 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Boston University
Collaborators
Novartis Pharmaceuticals, Pfizer, Otsuka Pharmaceutical Co., Ltd., University of California, San Francisco, Westat, National Institute of Allergy and Infectious Diseases (NIAID), University of Colorado, Denver, Harvard Medical School (HMS and HSDM), National Lung Hospital, Vietnam, De La Salle Health Sciences Institute, Philippines

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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: Describe the relationship between the duration of the experimental regimen and the proportion of participants with sustained cure at 76 weeks after randomization without treatment failure or relapse. Describe the relationship between baseline prognostic risk strata and sustained cure at 76 weeks after randomization without treatment failure or relapse. Evaluate the association between novel biologic markers and sustained cure at 76 weeks after randomization without treatment failure or relapse. Secondary Objectives: Identify the shortest duration of the study regimen that has acceptable safety and efficacy for a Phase 3 clinical trial of the DRAMATIC regimen for treatment of MDR-TB. Describe the frequency, magnitude, time course of and risk factors for QTc prolongation associated with the study regimen. Demonstrate the feasibility and efficiency of implementing the new duration-randomized design in a multi-centre randomized trial of drug-resistant TB. Determine if time to sputum culture conversion predicts optimal duration of treatment when stratified by extent of disease. Describe the relationship between the duration of the experimental regimen and the proportion of participants with sustained cure at 104 weeks after randomization without treatment failure or relapse. Assess vital status at 132 weeks post randomization. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Multidrug-Resistant
Keywords
bedaquiline (BDQ), delamanid (DLM), linezolid (LZD), levofloxacin (LFX), clofazimine (CF)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
220 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Investigational: DRAMATIC-16 weeks
Arm Type
Experimental
Arm Description
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 1200 mg PO QD, Initial 8 weeks only
Arm Title
Investigational: DRAMATIC-24 weeks
Arm Type
Experimental
Arm Description
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 1200 mg PO QD, Initial 8 weeks only
Arm Title
Investigational: DRAMATIC-32 weeks
Arm Type
Experimental
Arm Description
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 1200 mg PO QD, Initial 8 weeks only
Arm Title
Investigational: DRAMATIC-40 weeks
Arm Type
Experimental
Arm Description
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 1200 mg PO QD, Initial 8 weeks only
Intervention Type
Drug
Intervention Name(s)
Delamanid
Other Intervention Name(s)
Deltyba
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Levofloxacin
Other Intervention Name(s)
Levaquin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Bedaquiline
Other Intervention Name(s)
Sirturo
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Clofazimine
Other Intervention Name(s)
Lamprene
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Linezolid
Other Intervention Name(s)
Zyvox
Intervention Description
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.
Primary Outcome Measure Information:
Title
Treatment Efficacy - Frequency of "successful treatment" outcomes
Description
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.
Time Frame
Week 76
Title
Treatment Safety - Frequency of participants with grade 3, 4, or 5 adverse events
Description
The primary outcome for safety are Grade 3, 4, or 5 adverse events
Time Frame
44 weeks
Secondary Outcome Measure Information:
Title
Efficacy outcome- Frequency of participants who survive
Description
Evaluate survival at 132 weeks post randomization.
Time Frame
Week 132

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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 <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 For women of childbearing potential, has a positive or indeterminate urine pregnancy test on the day of randomization. Has at screening a mean QTcF >450 msec based on three ECGs. At screening requires ongoing use of prohibited drugs indicated in section 4.2 At screening, has weight less than 33 Kg.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Pawandeep Kaur, MPH
Phone
(617) 358-2421
Email
kaurp@bu.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Charles Horsburgh, MD
Phone
(617) 358-3758
Email
rhorsbu@bu.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Charles Horsburgh, MD
Organizational Affiliation
Boston University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Payam Nahid, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
De La Salle Health Sciences Institute
City
Dasmariñas
ZIP/Postal Code
4114
Country
Philippines
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melchor Frias, MD
First Name & Middle Initial & Last Name & Degree
Melchor Frias, MD
First Name & Middle Initial & Last Name & Degree
Maria Tarcela Gler, MD
Facility Name
National Lung Hospital
City
Hanoi
Country
Vietnam
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Viet Nhung, MD
First Name & Middle Initial & Last Name & Degree
Viet Nhung, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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