Evaluating Newly Approved Drugs for Multidrug-resistant TB

NCT02754765 | Completed Phase 3 DMC

• 1 other identifier: MSF ERB-1555
• Study Type: interventional
• Target: 754
• Locations: 7 countries
• Sites: 12

Brief Summary

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).

Conditions

Tuberculosis, Multidrug-Resistant; Infection, Bacterial; Pulmonary Tuberculoses

Keywords

bedaquiline; delamanid; linezolid; clofazimine; tuberculosis; MDR-TB XDR-TB

Outcome Measures

Primary Outcomes (1)

• Week 73 Efficacy

  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.

  Week 73 after randomization

Secondary Outcomes (9)

• Week 104 Efficacy

  Week 104 after randomization

• Early Treatment Response (culture conversion)

  Week 8 after randomization

• Week 39 Efficacy

  Week 39 after randomization

• Week 73 Survival

  Week 73 after randomization

• Week 104 Survival

  Week 104 after randomization

Study Arms (6)

endTB regimen 1 (BeLiMoZ)

EXPERIMENTAL

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. Subjects will undergo a linezoilid dose reduction randomization to either 300mg daily or 600mg three times a week after 16 weeks of treatment or after a linezolid-related AE requiring dose reduction, whichever is earlier.

Drug: Bedaquiline; Drug: Moxifloxacin; Drug: Linezolid; Drug: Pyrazinamide

endTB regimen 2 (BeLiCLeZ)

EXPERIMENTAL

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. Subjects will undergo a linezoilid dose reduction randomization to either 300mg daily or 600mg three times a week after 16 weeks of treatment or after a linezolid-related AE requiring dose reduction, whichever is earlier.

Drug: Bedaquiline; Drug: Clofazimine; Drug: Levofloxacin; Drug: Linezolid; Drug: Pyrazinamide

endTB regimen 3 (BeDeLiLeZ)

EXPERIMENTAL

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. Subjects will undergo a linezoilid dose reduction randomization to either 300mg daily or 600mg three times a week after 16 weeks of treatment or after a linezolid-related AE requiring dose reduction, whichever is earlier.

Drug: Bedaquiline; Drug: Delamanid; Drug: Levofloxacin; Drug: Linezolid; Drug: Pyrazinamide

endTB regimen 4 (DeLiCLeZ)

EXPERIMENTAL

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. Subjects will undergo a linezoilid dose reduction randomization to either 300mg daily or 600mg three times a week after 16 weeks of treatment or after a linezolid-related AE requiring dose reduction, whichever is earlier.

Drug: Delamanid; Drug: Clofazimine; Drug: Levofloxacin; Drug: Linezolid; Drug: Pyrazinamide

endTB regimen 5 (DeCMoZ)

EXPERIMENTAL

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; Drug: Clofazimine; Drug: Moxifloxacin; Drug: Pyrazinamide

endTB regimen 6 (Control)

ACTIVE COMPARATOR

endTB regimen 6 is the control regimen.

Drug: Control arm MDR-TB regimen, consistent with WHO guidelines

Interventions

Bedaquiline DRUG

Also known as: Sirturo

endTB regimen 1 (BeLiMoZ); endTB regimen 2 (BeLiCLeZ); endTB regimen 3 (BeDeLiLeZ)

Delamanid DRUG

Also known as: Deltyba, OPC-67683

endTB regimen 3 (BeDeLiLeZ); endTB regimen 4 (DeLiCLeZ); endTB regimen 5 (DeCMoZ)

Clofazimine DRUG

Also known as: Lamprene

endTB regimen 2 (BeLiCLeZ); endTB regimen 4 (DeLiCLeZ); endTB regimen 5 (DeCMoZ)

Levofloxacin DRUG

endTB regimen 2 (BeLiCLeZ); endTB regimen 3 (BeDeLiLeZ); endTB regimen 4 (DeLiCLeZ)

Moxifloxacin DRUG

endTB regimen 1 (BeLiMoZ); endTB regimen 5 (DeCMoZ)

Linezolid DRUG

endTB regimen 1 (BeLiMoZ); endTB regimen 2 (BeLiCLeZ); endTB regimen 3 (BeDeLiLeZ); endTB regimen 4 (DeLiCLeZ)

Pyrazinamide DRUG

endTB regimen 1 (BeLiMoZ); endTB regimen 2 (BeLiCLeZ); endTB regimen 3 (BeDeLiLeZ); endTB regimen 4 (DeLiCLeZ); endTB regimen 5 (DeCMoZ)

Control arm MDR-TB regimen, consistent with WHO guidelines DRUG

Control arm MDR-TB regimen, consistent WHO guidelines

endTB regimen 6 (Control)

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• A patient will be eligible for randomization if s/he:
• Has documented pulmonary tuberculosis due to strains of M. tuberculosis resistant to rifampin (RIF) and susceptible to fluoroquinolones, diagnosed by validated rapid molecular test;
• Is ≥ 15 years of age;
• Is willing to use contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilized must agree to use contraception unless their partner has had a vasectomy; men who have not had a vasectomy must agree to use condoms;
• Provides informed consent for study participation; additionally a legal representative of patients considered minor per local laws should also provide consent;
• Lives in a dwelling that can be located by study staff and expects to remain in the area for the duration of the study.

You may not qualify if:

• A patient will not be eligible for randomization if s/he:
• Has known allergies or hypersensitivity to any of the investigational drugs;
• Is known to be pregnant or is unwilling or unable to stop breast-feeding an infant;
• Is unable to comply with treatment or follow-up schedule;
• Any condition (social or medical) which, in the opinion of the site principal investigator, would make study participant unsafe;
• 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 definition151 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 definition149 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.
• 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;

Sponsors & Collaborators

• Médecins Sans Frontières, France: lead
• Partners in Health: collaborator
• Harvard Medical School (HMS and HSDM): collaborator
• Epicentre: collaborator
• Institute of Tropical Medicine, Belgium: collaborator
• Socios En Salud, Peru: collaborator
• Interactive Research and Development: collaborator

Study Sites (12)

National Center for Tuberculosis and Lung Diseases

Tbilisi, 0101, Georgia

Location

Aundh Chest Hospital

Pune, India

Location

City Centre of Phthisiopulmonology

Almaty, 020000, Kazakhstan

Location

Center of Phthisiopulmonology of Almaty Health Department

Almaty, 050030, Kazakhstan

Location

National Center for Tuberculosis Problems

Almaty, Kazakhstan

Location

Partners In Health Lesostho

Maseru, Lesotho

Location

The Indus Hospital

Karachi, Pakistan

Location

Institute of Chest Disease,

Kotri, Pakistan

Location

Centro de Investigación del Hospital Nacional Hipólito Unanue

Lima, 1390, Peru

Location

Centro de Investigación de Enfermedades Neumológicas del Hospital Nacional Sergio Bernales

Lima, Peru

Location

Hospital Nacional Dos de Mayo Parque Historia de la Medicina

Lima, Peru

Location

Medecins Sans Frontieres Belgium

Khayelitsha, 7784, South Africa

Location

Related Publications (4)

• Guglielmetti L, Khan U, Velasquez GE, Gouillou M, Abubakirov A, Baudin E, Berikova E, Berry C, Bonnet M, Cellamare M, Chavan V, Cox V, Dakenova Z, de Jong BC, Ferlazzo G, Karabayev A, Kirakosyan O, Kiria N, Kunda M, Lachenal N, Lecca L, McIlleron H, Motta I, Toscano SM, Mushtaque H, Nahid P, Oyewusi L, Panda S, Patil S, Phillips PPJ, Ruiz J, Salahuddin N, Garavito ES, Seung KJ, Ticona E, Trippa L, Vasquez DEV, Wasserman S, Rich ML, Varaine F, Mitnick CD; endTB Clinical Trial Team. Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis. N Engl J Med. 2025 Jan 30;392(5):468-482. doi: 10.1056/NEJMoa2400327.

  PMID: 39879593 DERIVED

• Hewison C, Khan U, Bastard M, Lachenal N, Coutisson S, Osso E, Ahmed S, Khan P, Franke MF, Rich ML, Varaine F, Melikyan N, Seung KJ, Adenov M, Adnan S, Danielyan N, Islam S, Janmohamed A, Karakozian H, Kamene Kimenye M, Kirakosyan O, Kholikulov B, Krisnanda A, Kumsa A, Leblanc G, Lecca L, Nkuebe M, Mamsa S, Padayachee S, Thit P, Mitnick CD, Huerga H. Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort. Clin Infect Dis. 2022 Sep 29;75(6):1006-1013. doi: 10.1093/cid/ciac019.

  PMID: 35028659 DERIVED

• Guglielmetti L, Ardizzoni E, Atger M, Baudin E, Berikova E, Bonnet M, Chang E, Cloez S, Coit JM, Cox V, de Jong BC, Delifer C, Do JM, Tozzi DDS, Ducher V, Ferlazzo G, Gouillou M, Khan A, Khan U, Lachenal N, LaHood AN, Lecca L, Mazmanian M, McIlleron H, Moschioni M, O'Brien K, Okunbor O, Oyewusi L, Panda S, Patil SB, Phillips PPJ, Pichon L, Rupasinghe P, Rich ML, Saluhuddin N, Seung KJ, Tamirat M, Trippa L, Cellamare M, Velasquez GE, Wasserman S, Zimetbaum PJ, Varaine F, Mitnick CD. Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial. Trials. 2021 Sep 25;22(1):651. doi: 10.1186/s13063-021-05491-3.

  PMID: 34563240 DERIVED

• Seung KJ, Khan P, Franke MF, Ahmed S, Aiylchiev S, Alam M, Putri FA, Bastard M, Docteur W, Gottlieb G, Hewison C, Islam S, Khachatryan N, Kotrikadze T, Khan U, Kumsa A, Lecca L, Tassew YM, Melikyan N, Naing YY, Oyewusi L, Rich M, Wanjala S, Yedilbayev A, Huerga H, Mitnick CD. Culture Conversion at 6 Months in Patients Receiving Delamanid-containing Regimens for the Treatment of Multidrug-resistant Tuberculosis. Clin Infect Dis. 2020 Jul 11;71(2):415-418. doi: 10.1093/cid/ciz1084.

  PMID: 31676905 DERIVED

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant; Bacterial Infections; Tuberculosis, Pulmonary; Tuberculosis

Interventions

bedaquiline; OPC-67683; Clofazimine; Levofloxacin; Moxifloxacin; Linezolid; Pyrazinamide

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

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

Study Officials

• Lorenzo Guglielmetti, MD

  Médecins Sans Frontières, France

  PRINCIPAL INVESTIGATOR

• Carole Mitnick, Sc.D

  Harvard Medical School (HMS and HSDM)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2016
• First Posted: April 28, 2016
• Study Start: December 1, 2016
• Primary Completion: June 1, 2023
• Study Completion: June 1, 2023
• Last Updated: February 10, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: From Q4 2024 and will last 5 years renewable.
• Access Criteria: * proposal has scientific value / the scientific question addresses a knowledge gap and avoids duplication without added value and unnecessary competition, and benefits the wider public health community * the data requested must be capable of answering the research question, and each variable requested must be required for the successful completion of the research * the methodology proposed to answer the research question must be sound * conform to the Data Access Guidelines, Ethics Framework, and Conflict of Interest Policy (see on website https://endtb.org/data-sharing-initiative)

Locations

LE (1); GE (1); PA (2); ZA (1); IN (1); PE (3); KA (3)