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

NCT ID: NCT03896685

Last Updated: 2025-02-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 323 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-04-06
• Study Completion Date: 2024-12-31

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.

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 country and 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-disease phenotype and treatment response. 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%.

Conditions

Tuberculosis, Multidrug-Resistant; Tuberculosis; Pulmonary Tuberculoses; Mycobacterial Infections; Bacterial Infections; Gram-Positive Bacterial Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Bedaquiline 100 MG

Intervention Type: DRUG

Bedaquiline: 400 mg QD x 2 weeks, followed by 200 mg 3x/week

Delamanid 50 MG Oral Tablet

Intervention Type: DRUG

Delamanid: 100 mg BID

Clofazimine 100 MG Oral Capsule

Intervention Type: DRUG

Clofazimine: 100 mg QD

Linezolid 600Mg Tab

Intervention Type: DRUG

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

endTB-Q: Control arm

endTB-Q is the control regimen, designed according to latest World Health Organization guidelines.

Group Type: ACTIVE_COMPARATOR

Control arm MDR-TB regimen, designed according to latest WHO guidelines

Intervention Type: DRUG

Control arm MDR-TB regimen, designed according to latest WHO guidelines (might include bedaquiline, delamanid, linezolid, clofazimine, or all of these drugs).

Interventions

Bedaquiline 100 MG

Bedaquiline: 400 mg QD x 2 weeks, followed by 200 mg 3x/week

Intervention Type: DRUG

Delamanid 50 MG Oral Tablet

Delamanid: 100 mg BID

Intervention Type: DRUG

Clofazimine 100 MG Oral Capsule

Clofazimine: 100 mg QD

Intervention Type: DRUG

Linezolid 600Mg Tab

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

Intervention Type: 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).

Intervention Type: DRUG

Other Intervention Names

TMC207

Eligibility 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. Patients with RIF-resistant TB who are unable to tolerate fluoroquinolones (history of severe adverse events, allergies, hypersensitivity) are also eligible, regardless of resistance/susceptibility to fluoroquinolones;

2. Is ≥15 years of age;

3. 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;

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; Unless otherwise specified, Grade 4 result as defined by the MSF Severity Scale 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 greater than or equal to 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. Concurrent participation in another trial of any medication used or being studied for TB treatment, as defined in cited documents.

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.

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Partners in Health

OTHER

Sponsor Role: collaborator

Harvard Medical School (HMS and HSDM)

OTHER

Sponsor Role: collaborator

Epicentre

OTHER

Sponsor Role: collaborator

Institute of Tropical Medicine, Belgium

OTHER

Sponsor Role: collaborator

Socios En Salud, Peru

UNKNOWN

Sponsor Role: collaborator

Interactive Research and Development

OTHER

Sponsor Role: collaborator

University of San Francisco

OTHER

Sponsor Role: collaborator

Médecins Sans Frontières, France

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lorenzo Guglielmetti, MD

Role: PRINCIPAL_INVESTIGATOR

Médecins Sans Frontières, France

Carole Mitnick, Sc.D

Role: PRINCIPAL_INVESTIGATOR

Harvard Medical School (HMS and HSDM)

Locations

Aundh Chest Hospital

Pune, , India

National Center for Tuberculosis Problems

Almaty, , Kazakhstan

State Municipal Enterprise on the right of economic management "City Centre of Phthisiopulmonology" of Nur-sultan city's administration

Almaty, , Kazakhstan

Partners In Health Lesostho

Maseru, , Lesotho

The Indus Hospital

Karachi, , Pakistan

Institute of Chest Disease,

Kotri, , Pakistan

Centro de Investigación del Hospital Nacional Hipólito Unanue

Lima, , Peru

Centro de Investigación de Enfermedades Neumológicas del Hospital Nacional Sergio Bernales

Lima, , Peru

Hanoi Lung Hospital

Hanoi, , Vietnam

Pham Ngoc Thach Hospital

Ho Chi Minh City, , Vietnam

Countries

India; Kazakhstan; Lesotho; Pakistan; Peru; Vietnam

References

Guglielmetti L, Khan U, Velasquez GE, Gouillou M, Ali MH, Amjad S, Kamal F, Abubakirov A, Ardizzoni E, Baudin E, Bektassov S, Berry C, Bonnet M, Chavan V, Coutisson S, Dakenova Z, de Jong BC, Dinh LV, Ferlazzo G, Kirakosyan O, Lachenal N, Lecca L, McIlleron H, Mikanda KK, Mucching-Toscano S, Mulders W, Mushtaque H, Nahid P, Nguyen DV, Nguyen NV, Oyewusi L, Motta I, Panda S, Patil S, Pham TH, Phan DT, Phan HTT, Phillips PPJ, Ruiz J, Rupasinghe P, Salahuddin N, Sanchez-Garavito E, Seung KJ, Asfaw MT, Vargas Vasquez D, Rich ML, Varaine F, Mitnick CD; endTB-Q Clinical Trial Team. Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): an open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial. Lancet Respir Med. 2025 Sep;13(9):809-820. doi: 10.1016/S2213-2600(25)00194-8. Epub 2025 Jul 16.

Reference Type: DERIVED

PMID: 40683298 (View on PubMed)

Patil SB, Tamirat M, Khazhidinov K, Ardizzoni E, Atger M, Austin A, Baudin E, Bekhit M, Bektasov S, Berikova E, Bonnet M, Caboclo R, Chaudhry M, Chavan V, Cloez S, Coit J, Coutisson S, Dakenova Z, De Jong BC, Delifer C, Demaisons S, Do JM, Dos Santos Tozzi D, Ducher V, Ferlazzo G, Gouillou M, Khan U, Kunda M, Lachenal N, LaHood AN, Lecca L, Mazmanian M, McIlleron H, Moreau M, Moschioni M, Nahid P, Osso E, Oyewusi L, Panda S, Paquet A, Thuong Huu P, Pichon L, Rich ML, Rupasinghe P, Salahuddin N, Sanchez Garavito E, Seung KJ, Velasquez GE, Vallet M, Varaine F, Yuya-Septoh FJ, Mitnick CD, Guglielmetti L. Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial. Trials. 2023 Nov 30;24(1):773. doi: 10.1186/s13063-023-07701-6.

Reference Type: DERIVED

PMID: 38037119 (View on PubMed)

Provided Documents

Document Type: Informed Consent Form: endTB-Q_Research Screening Adult Consent_Assent form V4.3

View Document

Document Type: Informed Consent Form: endTB-Q_Research Screening Parental Consent form V4.3

View Document

Document Type: Informed Consent Form: endTB-Q_Research Adult Consent_Assent form v4.3

View Document

Document Type: Informed Consent Form: endTB-Q_Research Parental Consent form v4.3

View Document

Document Type: Informed Consent Form: endTB-Q_Pregnant Partner Consent form V4.3

View Document

Document Type: Informed Consent Form: endTB-Q_Treatment during pregnancy_Consent form V4.3

View Document

Other Identifiers

MSF ERB-1761

Identifier Type: -

Identifier Source: org_study_id