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Evaluating Newly Approved Drugs in Combination Regimens for Multidrug-Resistant TB With Fluoroquinolone Resistance (endTB-Q) (endTB-Q)

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ClinicalTrials.gov Identifier: NCT03896685
Recruitment Status : Not yet recruiting
First Posted : April 1, 2019
Last Update Posted : August 28, 2019
Sponsor:
Collaborators:
Partners in Health
Harvard Medical School
Epicentre
Institute of Tropical Medicine, Belgium
Socios En Salud, Peru
Interactive Research and Development
Information provided by (Responsible Party):
Médecins Sans Frontières, France

Brief Summary:
endTB-Q Clinical Trial is a Phase III, randomized, controlled, open-label, non-inferiority, multi-country trial evaluating the efficacy and safety of two new, all-oral, shortened regimens for multidrug-resistant tuberculosis (MDR-TB) with fluoroquinolone resistance.

Condition or disease Intervention/treatment Phase
Tuberculosis, Multidrug-Resistant Tuberculosis Tuberculosis, Pulmonary Mycobacterium Infections Bacterial Infections Gram-Positive Bacterial Infections Drug: Bedaquiline 100 MG Drug: Delamanid 50 MG Oral Tablet Drug: Clofazimine Pill Drug: Linezolid Pill Drug: Control arm MDR-TB regimen, designed according to latest WHO guidelines Phase 3

Detailed Description:

This is a Phase III, randomized, controlled, open-label, multi-country trial evaluating the efficacy of new combination regimens for treatment of fluoroquinolone-resistant MDR-TB.

Regimens examined combine newly approved drugs bedaquiline and delamanid with existing drugs known to be active against Mycobacterium tuberculosis (linezolid and clofazimine). The study will enroll in parallel across 1 experimental and 1 standard-of-care control arms, in a 2:1 ratio. Randomization will be stratified by extent-of-TB-disease phenotype. In the experimental arm, treatment will be for 24 or 39 weeks; duration will be assigned according to extent-of-TB-diseasephenotype. In the control arm, treatment will be delivered according to WHO guidelines (and local practice); duration will be variable. Trial participation in both arms will last at least until Week 73, and up to Week 104.

Non-inferiority will be established for the experimental arm if the lower bound of the one-sided 97.5% confidence interval around the difference in favorable outcome between the control and experimental arms is greater than or equal to -12%.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 324 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluating Newly Approved Drugs in Combination Regimens for Multidrug-Resistant TB With Fluoroquinolone Resistance (endTB-Q)
Estimated Study Start Date : February 2020
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: endTB-Q: BeDeCLi 24 or 39 weeks
endTB-Q regimen: bedaquiline-delamanid-linezolid-clofazimine (BeDeCLi). Subjects who are randomized to this arm will be assigned to duration of 24 or 39 weeks , according to the participant's extent-of-TB-disease phenotype. Participants may take as long as 32 weeks to complete all doses of a 24-week treatment regimen, and up to 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of the experimental regimens will be oral and weight based.
Drug: Bedaquiline 100 MG
Bedaquiline: 400 mg QD x 2 weeks, followed by 200 mg 3x/week
Other Name: TMC207

Drug: Delamanid 50 MG Oral Tablet
Delamanid: 100 mg BID

Drug: Clofazimine Pill
Clofazimine: 100 mg QD

Drug: Linezolid Pill
Linezolid: 600 mg QD up to Week 16, followed by 300 mg QD or 600 mg 3x/week according to a secondary randomization

Active Comparator: endTB-Q: Control arm
endTB-Q is the control regimen, designed according to latest World Health Organization guidelines.
Drug: Control arm MDR-TB regimen, designed according to latest WHO guidelines
Control arm MDR-TB regimen, designed according to latest WHO guidelines (might include bedaquiline, delamanid, linezolid, clofazimine, or all of these drugs).




Primary Outcome Measures :
  1. Week 73 Efficacy: Proportion of participants with favorable outcome at Week 73 [ Time Frame: Week 73 after randomization ]

    Proportion of participants with favorable outcome at Week 73. A participant's outcome will be classified as favorable at Week 73 if the outcome is not classified as unfavorable, and one of the following is true:

    1. The last two culture results are negative. These two cultures must be taken from sputum samples collected on separate visits, the latest between Week 65 and Week 73;
    2. The last culture result (from a sputum sample collected between Week 65 and Week 73) is negative; and either there is no other post-baseline culture result or the penultimate culture result is positive due to laboratory cross contamination; and bacteriological, radiological and clinical evolution is favorable;
    3. There is no culture result from a sputum sample collected between Week 65 and Week 73 or the result of that culture is positive due to laboratory cross contamination; and the most recent culture result is negative; and bacteriological, radiological and clinical evolution is favorable.


Secondary Outcome Measures :
  1. Week 104 Efficacy: Proportion of participants with favorable outcome at Week 104 [ Time Frame: Week 104 after randomization ]

    Proportion of participants with favorable outcome at Week 104. A participant's outcome will be classified as favorable at Week 104 if the outcome is not classified as unfavorable, and one of the following is true:

    1. The last two cultures are negative. These two cultures must be from sputum samples collected on separate visits, the latest between Week 97 and Week 104;
    2. The last culture result (from a sputum sample collected between Week 97 and Week 104) is negative; and either there is no other post-baseline culture result or the penultimate culture result is positive due to laboratory cross contamination; and bacteriological, radiological and clinical evolution is favorable;
    3. There is no culture result from a sputum sample collected between Week 97 and Week 104 or the result of that culture is positive due to laboratory cross contamination; and the most recent culture result is negative; and bacteriological, radiological and clinical evolution is favorable.

  2. Early Treatment Response (culture conversion) [ Time Frame: Week 8 after randomization ]
    1. Proportion of patients with culture conversion assessed in MGIT system (and LJ where possible): 2 consecutive negative cultures from specimens collected at 2 different visits; if there is a missing or contaminated culture between 2 negatives, the definition of conversion is still met;
    2. Time to culture conversion: assessed in MGIT system (and LJ where possible): time from treatment initiation to first of 2 consecutive negative cultures; if there is a missing or contaminated culture between 2 negatives, the definition of conversion is still met;
    3. Change in time to positivity (TTP) in MGIT over first 8 weeks.

  3. Week 39 Efficacy: Proportion of participants with favorable outcome at Week 39 [ Time Frame: Week 39 after randomization ]
    Proportion of participants with favorable outcome at Week 39. A participant's outcome will be classified as favorable at Week 39 if all culture results from samples collected between Week 36 and Week 39 are negative and the outcome is not classified as unfavorable.

  4. Week 24 Efficacy: Proportion of participants with favorable outcome at Week 24 [ Time Frame: Week 24 after randomization ]
    Proportion of participants with favorable outcome at Week 24. A participant's outcome will be classified as favorable at Week 24 if all culture results from samples collected between Week 20 and Week 24 are negative and the outcome is not classified as unfavorable.

  5. Week 73 Failure/Relapse [ Time Frame: Week 73 after randomization ]

    Proportion of participants with treatment failure/relapse. A participant's outcome will be classified as failure/relapse at Week 73 if:

    1. In an experimental arm, addition or replacement of one or more drugs;
    2. In the control arm, addition or replacement of two or more drugs;
    3. Initiation of a new MDR-TB regimen after the end of the allocated study regimen and before Week 73;
    4. At least one of the last two cultures, the latest between Week 65 and 73, is positive in the absence of cross contamination;
    5. The last culture result between Week 65 and 73 is negative; and: there is no other post-baseline culture result or the penultimate culture is positive due to cross contamination; and bacteriological, radiological or clinical evolution is unfavorable;
    6. There is no culture result between Week 65 and 73 or it is positive due to cross contamination; and: the most recent culture is negative; and bacteriological, radiological or clinical evolution is unfavorable.

  6. Week 104 Failure/Relapse [ Time Frame: Week 104 after randomization ]

    Proportion of participants with treatment failure/relapse. A participant's outcome will be classified as failure/relapse at Week 104 if:

    1. In an experimental arm, addition or replacement of one or more drugs;
    2. In the control arm, addition or replacement of two or more drugs;
    3. Initiation of a new MDR-TB treatment regimen after the end of the allocated study regimen and before Week 104;
    4. At least one of the last two cultures, the latest between Week 97 and 104, is positive in the absence of cross contamination;
    5. The last culture result between Week 97 and 104 is negative; and: there is no other post-baseline culture result or the penultimate culture is positive due to cross contamination; and bacteriological, radiological or clinical evolution is unfavorable;
    6. There is no culture result between Week 97 and 104 or it is positive due to cross contamination; and: the most recent culture is negative; and bacteriological, radiological or clinical evolution is unfavorable.

  7. Week 73 Survival [ Time Frame: Week 73 after randomization ]
    At 73 weeks, the proportion of patients who died of any cause

  8. Week 104 Survival [ Time Frame: Week 104 after randomization ]
    At 104 weeks, the proportion of patients who died of any cause

  9. Week 73 AEs and SAEs [ Time Frame: Week 73 after randomization ]
    The proportion of participants with grade 3 or greater AEs and serious adverse events (SAEs) of any grade by 73 weeks

  10. Week 104 AEs and SAEs [ Time Frame: Week 104 after randomization ]
    The proportion of participants with grade 3 or greater AEs and serious adverse events (SAEs) of any grade by 104 weeks

  11. Week 73 AESIs [ Time Frame: Week 73 after randomization ]
    The proportion of participants with adverse events of special interest (AESIs) by 73 weeks

  12. Week 104 AESIs [ Time Frame: Week 104 after randomization ]
    The proportion of participants with adverse events of special interest (AESIs) by 104 weeks



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

Inclusion Criteria:

  1. Has documented pulmonary tuberculosis due to strains of M. tuberculosis resistant to rifampin (RIF) and not susceptible to fluoroquinolones, according to a validated rapid molecular test.
  2. Is ≥15 years of age;
  3. Is willing to use effective contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilized must agree to use two methods of contraception (e.g., a hormonal method and a barrier method) unless their partner has had a vasectomy; men who have not had a vasectomy must agree to use condoms;
  4. Provides informed consent for study participation; additionally a legal representative of patients considered minor per local laws should also provide consent;
  5. Lives in a dwelling that can be located by study staff and expects to remain in the area for the duration of the study.

Exclusion Criteria:

1. Has known allergies or hypersensitivity to any of the investigational drugs; 2. Is known to be pregnant or is unwilling or unable to stop breastfeeding an infant; 3. Is unable to comply with treatment or follow-up schedule; 4. Has any condition (social or medical) which, in the opinion of the site principal investigator, would make study participant unsafe; 5. a. Has had exposure (intake of the drug for 30 days or more) in the past five years to bedaquiline, delamanid, linezolid, or clofazimine, or has proven or likely resistance to bedaquiline, delamanid, linezolid, or clofazimine (e.g., household contact of a DR-TB index case who died or experienced treatment failure after treatment containing bedaquiline, delamanid, linezolid, or clofazimine or had resistance to one of the listed drugs); exposure to other anti-TB drugs is not a reason for exclusion.

b. Has received second-line drugs for 15 days or more prior to screening visit date in the current MDR/RR-TB treatment episode. Exceptions include:

  1. patients whose treatment has failed according to the WHO definition and who are being considered for a new treatment regimen;
  2. patients starting a new treatment regimen after having been "lost to follow-up" according to the WHO definition and,
  3. patients in whom treatment failure is suspected (but not confirmed according to WHO definition), who are being considered for a new treatment regimen, and for whom the Clinical Advisory Committee (CAC) consultation establishes eligibility.

6. Has one or more of the following:

  • Hemoglobin ≤7.9 g/dL;
  • Uncorrectable electrolytes disorders:

    • Total Calcium <7.0 mg/dL (1.75 mmol/L);
    • Potassium <3.0 mEq/L (3.0 mmol/L) or ≥6.0 mEq/L (6.0 mmol/L);
    • Magnesium <0.9 mEq/L (0.45 mmol/L);
  • Serum creatinine >3 x ULN;
  • Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 x ULN;
  • Total bilirubin ≥3 x ULN;
  • Albumin <2.8 g/dL; Unless otherwise specified, Grade 4 result as defined by the MSF Severity Scale (Appendix 2) on any of the screening laboratory tests.

    7. Has cardiac risk factors defined as:

  • An arithmetic average of the two ECGs with highest QTcF intervals of greater than or equal to 450 ms. Retesting to reassess eligibility will be allowed using an unscheduled visit during the screening phase;
  • Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome);
  • Electrocardiographic evidence of either:

    • Complete left bundle branch block or right bundle branch block; OR
    • Incomplete left bundle branch block or right bundle branch block and QRS complex duration >120 msec on at least one ECG;
  • Having a pacemaker implant;
  • Congestive heart failure;
  • Evidence of second or third degree heart block;
  • Bradycardia as defined by sinus rate less than 50 bpm;
  • Personal or family history of Long QT Syndrome;
  • Personal history of arrhythmic cardiac disease, with the exception of sinus arrhythmia;
  • Personal history of syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes).

    8. Is currently taking part in another trial of a medicinal product;

    9. Is taking any medication that is contraindicated with the medicines in the trial regimen which cannot be stopped (with or without replacement) or requires a wash-out period longer than 2 weeks.


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): NCT03896685


Contacts
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Contact: Melchior Atger +33 1 40 21 54 12 endtb.clinicaltrial@paris.msf.org

Locations
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India
ICMR-National AIDS Research Center Not yet recruiting
Pune, India
Contact: Hanif Shaikh       msfocb-india-EndTB-coord@brussels.msf.org   
Kazakhstan
National Center for Tuberculosis Problems
Almaty, Kazakhstan
Lesotho
Partners In Health Lesostho Not yet recruiting
Maseru, Lesotho
Contact: Sesomo Mohale       smohale@pih.org   
Pakistan
The Indus Hospital Not yet recruiting
Karachi, Pakistan
Contact: Meherunissa Hamid       meherunissa.hamid@ghd.ihn.org.pk   
Peru
Socios En Salud Not yet recruiting
Lima, Peru
Contact: Fanny Garcia Velarde       fgarcia_ses@pih.org   
South Africa
Medecins Sans Frontieres Belgium Not yet recruiting
Khayelitsha, South Africa, 7784
Contact: Jared Borain       msfocb-khayelitsha-endtb@brussels.msf.org   
Sponsors and Collaborators
Médecins Sans Frontières, France
Partners in Health
Harvard Medical School
Epicentre
Institute of Tropical Medicine, Belgium
Socios En Salud, Peru
Interactive Research and Development

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Responsible Party: Médecins Sans Frontières, France
ClinicalTrials.gov Identifier: NCT03896685     History of Changes
Other Study ID Numbers: MSF ERB-1761
First Posted: April 1, 2019    Key Record Dates
Last Update Posted: August 28, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Médecins Sans Frontières, France:
bedaquiline
delamanid
linezolid
clofazimine
tuberculosis
MDR-TB
XDR-TB
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Tuberculosis
Bacterial Infections
Mycobacterium Infections
Tuberculosis, Pulmonary
Gram-Positive Bacterial Infections
Tuberculosis, Multidrug-Resistant
Actinomycetales Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Linezolid
Bedaquiline
Diarylquinolines
Fluoroquinolones
Clofazimine
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antitubercular Agents
Nucleic Acid Synthesis Inhibitors
Anti-Inflammatory Agents
Leprostatic Agents