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Evaluating Newly Approved Drugs for Multidrug-resistant TB (endTB)

This study is currently recruiting participants.
See Contacts and Locations
Verified August 2017 by Médecins Sans Frontières France
Sponsor:
Collaborators:
Partners in Health
Harvard Medical School
Epicentre
Institute of Tropical Medicine, Belgium
Ministry of Health, Kyrgyzstan
National Center for Tuberculosis Problems, Kazakhstan
Ministry of Health, Lesotho
National Center for Tuberculosis and Lung Diseases, Georgia
Socios En Salud, Peru
Information provided by (Responsible Party):
Médecins Sans Frontières France
ClinicalTrials.gov Identifier:
NCT02754765
First received: April 25, 2016
Last updated: August 4, 2017
Last verified: August 2017
  Purpose
endTB Clinical Trial a Phase III, randomized, controlled, open-label, non-inferiority, multi-country trial evaluating the efficacy and safety of five new, all-oral, shortened regimens for multidrug-resistant tuberculosis (MDR-TB).

Condition Intervention Phase
Tuberculosis, Multidrug-Resistant Drug: Bedaquiline Drug: Delamanid Drug: Clofazimine Drug: Levofloxacin Drug: Moxifloxacin Drug: Linezolid Drug: Pyrazinamide Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluating Newly Approved Drugs for Multidrug-resistant TB (endTB): A Clinical Trial

Resource links provided by NLM:


Further study details as provided by Médecins Sans Frontières France:

Primary Outcome Measures:
  • Week 73 Efficacy [ 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:

    • The last two culture results are negative. These two cultures must be taken from sputum samples collected on separate visits, the latest between weeks 65 and 73;
    • The last culture result (from a sputum sample collected between weeks 65 and 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;
    • There is no culture result from a sputum sample collected between weeks 65 and 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:
  • Week 104 Efficacy [ 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 weeks 97 and 104;
    2. The last culture result (from a sputum sample collected between weeks 97 and 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 weeks 97 and 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.

  • 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 8 weeks.

  • Week 39 Efficacy [ 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 the last culture result (from a sample collected between weeks 36 and 39) is negative; and the outcome is not classified as unfavorable.

    A participant's outcome will be classified as unfavorable at week 39 in case of:

    1. In the experimental arm, addition or replacement of one or more drugs;
    2. In the control arm, addition or replacement of two or more drugs;
    3. Death from any cause;
    4. At least one culture result (from a sample collected between weeks 36 and 39) is positive;
    5. The patient is not assessable because the last available culture result is from a sample collected before week 36.

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

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

  • Week 73 Safety [ 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

  • Week 104 Safety [ 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

  • Week 73 QTc interval prolongation [ Time Frame: Week 73 after randomization ]
    The proportion of patients with either QTc interval prolongation of ≥60 ms from baseline or QTc interval of > 500 ms by 73 weeks


Estimated Enrollment: 750
Actual Study Start Date: December 2016
Estimated Study Completion Date: April 2021
Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: endTB regimen 1 (BeLiMoZ)
Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based.
Drug: Bedaquiline
Other Name: Sirturo
Drug: Moxifloxacin Drug: Linezolid Drug: Pyrazinamide
Experimental: endTB regimen 2 (BeLiCLeZ)
Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based.
Drug: Bedaquiline
Other Name: Sirturo
Drug: Clofazimine
Other Name: Lamprene
Drug: Levofloxacin Drug: Linezolid Drug: Pyrazinamide
Experimental: endTB regimen 3 (BeDeLiLeZ)
Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based.
Drug: Bedaquiline
Other Name: Sirturo
Drug: Delamanid
Other Names:
  • Deltyba
  • OPC-67683
Drug: Levofloxacin Drug: Linezolid Drug: Pyrazinamide
Experimental: endTB regimen 4 (DeLiCLeZ)
Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based.
Drug: Delamanid
Other Names:
  • Deltyba
  • OPC-67683
Drug: Clofazimine
Other Name: Lamprene
Drug: Levofloxacin Drug: Linezolid Drug: Pyrazinamide
Experimental: endTB regimen 5 (DeCMoZ)
Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based.
Drug: Delamanid
Other Names:
  • Deltyba
  • OPC-67683
Drug: Clofazimine
Other Name: Lamprene
Drug: Moxifloxacin Drug: Pyrazinamide
Active Comparator: endTB regimen 6 (Control)
endTB regimen 6 is the control regimen.
Drug: Pyrazinamide

Detailed Description:

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

Regimens examined combine newly approved drugs bedaquiline and/or delamanid with existing drugs known to be active against Mycobacterium tuberculosis (linezolid, clofazimine, moxifloxacin or levofloxacin, and pyrazinamide). The study will enroll in parallel across 5 experimental and 1 standard-of-care control arms. Randomization will be outcome adapted using Bayesian interim analysis of efficacy endpoints. Experimental regimens will contain bedaquiline and/or delamanid and up to 4 companion drugs. Control-arm treatment may contain one of the following (bedaquiline or delamanid) and companion drugs, constructed and delivered according to local standard of care and consistent with WHO guidelines. Trial participation in all arms will be for 104 weeks post randomization. In the experimental arms, treatment will be for 39 weeks (participants in the experimental arms will be allowed up to 47 weeks to complete the 39-week treatment course) and post-treatment follow up for up to 65 additional weeks. In the control arm, treatment will be delivered according to local standard of care (in consistence with WHO guidance); duration will be variable, for approximately 86 weeks. Non-inferiority will be established for any 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%.

  Eligibility

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

Inclusion Criteria:

A patient will be eligible for randomization if s/he:

  1. Has documented pulmonary tuberculosis due to strains of M. tuberculosis resistant to rifampin (RIF) and susceptible to fluoroquinolones, diagnosed by 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:

A patient will not be eligible for randomization if s/he:

  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 breast-feeding an infant;
  3. Is unable to comply with treatment or follow-up schedule;
  4. Any condition (social or medical) which, in the opinion of the site principal investigator, would make study participant unsafe;
  5. Has had exposure in the past five years, or resistance to, bedaquiline, delamanid, linezolid, or clofazimine; exposure to other anti-TB drugs is not a reason for exclusion.
  6. Has one or more of the following:

    • Hemoglobin ≤ 7.9 g/dL;
    • Uncorrectable electrolytes disorders:
    • Calcium < 7.0 mg/dL;
    • Potassium < 3.0 or ≥6.0 mEq/L;
    • Magnesium < 0.9 mEq/L;
    • Serum creatinine > 3 x ULN;
    • Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 x ULN;
    • Total bilirubin ≥ 1.5 x ULN if accompanied by AST or ALT > ULN or total bilirubin ≥ 2 x ULN when other liver function results are in the normal range;
    • Albumin < 2.8 g/dL;
    • Grade 4 result on any of the specified laboratory tests as defined by the MSF Severity Scale.
  7. Has cardiac risk factors defined as:

    • A confirmed QTc interval of greater than or equal to 450 ms. Retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase;
    • Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome);
    • Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block;
    • 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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02754765

Contacts
Contact: Eva Chang 6174322114 eva_chang@hms.harvard.edu
Contact: Enoma Okunbor osarenoma_okunbor@hms.harvard.edu

Locations
Georgia
National Center for Tuberculosis and Lung Diseases Recruiting
Tbilisi, Georgia, 0101
Contact: Nino Kiria, MD       msff-tbilisi-endtb@paris.msf.org   
Principal Investigator: Nana Kiria, MD         
Kazakhstan
National Center for Tuberculosis Problems Recruiting
Almaty, Kazakhstan
Contact: Kanat Khazhidinov, MD       kkhazhidinov@pih.org   
Principal Investigator: Elmira Berikova, MD         
Kyrgyzstan
Osh Oblast Tuberculosis Hospital Not yet recruiting
Osh, Kyrgyzstan
Contact: Arnol Samiev, MD       msfch-osh-tb@geneva.msf.org   
Principal Investigator: Kauk Galina Vladimirovna, MD         
Lesotho
Partners In Health Lesostho Not yet recruiting
Maseru, Lesotho
Contact: Eva Chang       eva_chang@hms.harvard.edu   
Principal Investigator: Odunayo Johnson Alakaye, MBBS         
Peru
Socios En Salud Recruiting
Lima, Peru
Contact: Fanny Garcia Velarde       fgarcia_ses@pih.org   
Principal Investigator: Leo Lecca, MD         
Sponsors and Collaborators
Médecins Sans Frontières France
Partners in Health
Harvard Medical School
Epicentre
Institute of Tropical Medicine, Belgium
Ministry of Health, Kyrgyzstan
National Center for Tuberculosis Problems, Kazakhstan
Ministry of Health, Lesotho
National Center for Tuberculosis and Lung Diseases, Georgia
Socios En Salud, Peru
Investigators
Principal Investigator: Francis Varaine, MD Médecins Sans Frontières France
Principal Investigator: Carole Mitnick, Sc.D Harvard Medical School
  More Information

Responsible Party: Médecins Sans Frontières France
ClinicalTrials.gov Identifier: NCT02754765     History of Changes
Other Study ID Numbers: MSF ERB-1555
Study First Received: April 25, 2016
Last Updated: August 4, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Moxifloxacin
Levofloxacin
Ofloxacin
Linezolid
Pyrazinamide
Clofazimine
Bedaquiline
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anti-Infective Agents, Urinary
Renal Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Protein Synthesis Inhibitors
Antitubercular Agents
Anti-Inflammatory Agents
Leprostatic Agents

ClinicalTrials.gov processed this record on August 22, 2017