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

  • STATUS
    Recruiting
  • End date
    Dec 25, 2022
  • participants needed
    324
  • sponsor
    Médecins Sans Frontières, France
Updated on 25 January 2021
vasectomy
fluoroquinolones
linezolid
pulmonary tuberculosis
bedaquiline
delamanid
clofazimine
bedaquiline 100 mg
linezolid pill

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.

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%.

Details
Condition Tuberculosis, Pulmonary Disease, Bacterial Infection, drug-resistant tuberculosis, Mycobacterium, Mycobacterial infection, Pulmonary tuberculosis, Gram-Positive Bacterial Infections, Lung Disease, Bacterial Infections, tb (tuberculosis), bacterial disease
Treatment Bedaquiline 100 MG, Delamanid 50 MG Oral Tablet, Clofazimine Pill, Linezolid Pill, Control arm MDR-TB regimen, designed according to latest WHO guidelines
Clinical Study IdentifierNCT03896685
SponsorMédecins Sans Frontières, France
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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
Is 15 years of age
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
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

Exclusion Criteria

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
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
patients whose treatment has failed according to the WHO definition and who are being considered for a new treatment regimen
patients starting a new treatment regimen after having been "lost to follow-up" according to the WHO definition and
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
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
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)
Is currently taking part in another trial of a medicinal product
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
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