Clinical trial NCT03896685: Evaluating Newly Approved Drugs in Combination Regimens for Multidrug-Resistant TB With Fluoroquinolone Resistance (endTB-Q)
Official title: Evaluating Newly Approved Drugs in Combination Regimens for Multidrug-Resistant TB With Fluoroquinolone Resistance (endTB-Q)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberculosis, Multidrug-Resistant
Tuberculosis
Pulmonary Tuberculoses
Mycobacterial Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Keywords: bedaquiline
delamanid
linezolid
clofazimine
tuberculosis
MDR-TB
XDR-TB
Lead sponsor: Médecins Sans Frontières, France
Sponsor class: OTHER
Collaborators: name: Partners in Health
name: Harvard Medical School (HMS and HSDM)
name: Epicentre
name: Institute of Tropical Medicine, Belgium
name: Socios En Salud, Peru
name: Interactive Research and Development
name: University of San Francisco
First posted: 2019-04-01
Enrollment: 323
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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%.

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.

Primary outcomes:
measure: Week 73 Efficacy: Proportion of participants with favorable outcome at Week 73
timeFrame: Week 73 after randomization
Secondary outcomes:
measure: Week 104 Efficacy: Proportion of participants with favorable outcome at Week 104
timeFrame: Week 104 after randomization
measure: Early Treatment Response (culture conversion)
timeFrame: Week 8 after randomization
measure: Week 39 Efficacy: Proportion of participants with favorable outcome at Week 39
timeFrame: Week 39 after randomization
measure: Week 73 Failure/Relapse
timeFrame: Week 73 after randomization
measure: Week 104 Failure/Relapse
timeFrame: Week 104 after randomization
measure: Week 73 Survival
timeFrame: Week 73 after randomization
measure: Week 104 Survival
timeFrame: Week 104 after randomization
measure: Week 73 AEs and SAEs
timeFrame: Week 73 after randomization
measure: Week 104 AEs and SAEs
timeFrame: Week 104 after randomization
measure: Week 73 AESIs
timeFrame: Week 73 after randomization
measure: Week 104 AESIs
timeFrame: Week 104 after randomization
Other outcomes:
Locations:
city: Pune
country: India
facility: Aundh Chest Hospital
city: Almaty
country: Kazakhstan
facility: National Center for Tuberculosis Problems
city: Almaty
country: Kazakhstan
facility: State Municipal Enterprise on the right of economic management "City Centre of Phthisiopulmonology" of Nur-sultan city's administration
city: Maseru
country: Lesotho
facility: Partners In Health Lesostho
city: Karachi
country: Pakistan
facility: The Indus Hospital
city: Kotri
country: Pakistan
facility: Institute of Chest Disease,
city: Lima
country: Peru
facility: Centro de Investigación del Hospital Nacional Hipólito Unanue
city: Lima
country: Peru
facility: Centro de Investigación de Enfermedades Neumológicas del Hospital Nacional Sergio Bernales
city: Hanoi
country: Vietnam
facility: Hanoi Lung Hospital
city: Ho Chi Minh City
country: Vietnam
facility: Pham Ngoc Thach Hospital
Study officials:
affiliation: Médecins Sans Frontières, France
name: Lorenzo Guglielmetti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard Medical School (HMS and HSDM)
name: Carole Mitnick, Sc.D
role: PRINCIPAL_INVESTIGATOR
References: