Clinical trial NCT03086486: Various Doses and Durations of Linezolid Plus Bedaquiline & Pretomanid in Participants With Drug Resistant Tuberculosis
Official title: A Phase 3 Partially-blinded, Randomized Trial Assessing the Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB), Pre-XDR-TB or Treatment Intolerant or Non-responsive Multi-drug Resistant Tuberculosis (MDR-TB)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberculosis, Pulmonary
Tuberculosis, Multidrug-Resistant
Tuberculosis, MDR
Tuberculosis
Extensively Drug-Resistant Tuberculosis
Pre-XDR-TB
XDR-TB
Keywords: Tuberculosis
Multi Drug-Resistant Tuberculosis
Extensively Drug-Resistant Tuberculosis
Drug-Resistant Tuberculosis
Pretomanid
PA-824
Bedaquiline
Linezolid
NC-007
TB Alliance
pre-XDR-TB
Sirturo
Zyvox
ZeNix
Lead sponsor: Global Alliance for TB Drug Development
Sponsor class: OTHER
First posted: 2017-03-22
Enrollment: 181
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB.

Detailed description: A phase 3, multi-center, partially-blinded, randomized clinical trial in 4 parallel treatment groups. Bedaquiline and pretomanid treatment will not be blinded. Linezolid treatment dose and duration will be double-blinded.

Participants will have a screening period of up to 14 days and will be randomized to receive one of the 4 active treatment arms. Participants will be randomized to one of the 4 regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will utilize a randomization system using stratification with a random element to allocate participants evenly across the arms by HIV status and type of TB.

Each participant will receive 26 weeks of treatment. If participant's week 16 sputum sample is culture positive between the week 16 and week 26 treatment visits and their clinical condition suggests they may have an ongoing TB infection, Investigator may consider extending current treatment to 39 weeks. If the culture results between week 16 and week 26 are contaminated, missing or considered an isolated positive without clinical significance, available culture results should be used to make this decision. All decisions regarding treatment extension should be discussed with and approved by, in consultation with the Sponsor Medical Monitor before implementation. The treatment may also require modification due to toxicities. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for safety concerns.

Participants will be followed for 78 weeks after end of treatment.

Eligibility criteria: Inclusion Criteria:

* Male or female, aged 14 years or older.
* One of the following with documentation of culture positive or molecular test within 3 months of screening:

  * XDR-TB defined as resistance to rifamycins, a fluoroquinolone AND an injectable OR
  * Pre-XDR-TB with defined as resistance to rifamycins, and to a fluoroquinolone OR an injectable OR
  * MDR-TB with resistance to rifamycins, and either non-responsive or non-tolerant to current treatment.
* Of non-childbearing potential or willing to practice effective birth control methods.
* Complete informed consent form.

Exclusion criteria:

* Karnofsky score \< 60 at screening.
* Body mass index (BMI) \< 17 kg/m2
* Participants who are expected to require a surgical procedure (for Pulmonary TB).
* Any risk factor for QT prolongation
* Pregnant or breast-feeding
* Any planned contraindicated medicines or received more than 2 weeks of bedaquiline, linezolid or delamanid prior to first dose of IMP.
* A peripheral neuropathy of Grade 3 or 4, according to DMID. Or, participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator
* Any of the following lab toxicities/abnormalities:

  * Viral load \>1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who otherwise qualify for participation);
  * CD4+ count \< 100 cells/µL (HIV positive participants);
  * Serum potassium less than the lower limit of normal for the laboratory;
  * Hemoglobin \< 9.0 g/dL or 90g/L;
  * Platelets \<100,000/mm3 or \< 100 x 10\^9/L
  * Absolute neutrophil count (ANC) \< 1500/ mm3 or \< 1.5 x 10\^9/L
  * Aspartate aminotransferase (AST) and Alanini aminotransferase (ALT) Grade 3 or greater (\> 3.0 x ULN)
  * Total bilirubin greater than 1.5 x ULN
  * Direct bilirubin greater than ULN
  * Serum creatinine level greater than 1.5 times upper limit of normal
  * Albumin \<3.0 g/dl or \< 30 g/L

Primary outcomes:
measure: Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 26 Weeks After the End of Treatment
timeFrame: 26 weeks
Secondary outcomes:
measure: Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 78 Weeks After the End of Treatment.
timeFrame: 78 weeks
measure: Time to Sputum Culture Conversion to Negative Status Through the Treatment Period
timeFrame: 26 weeks
measure: Sputum Culture Conversion to Negative Status at End of Treatment for Those Positive at Baseline
timeFrame: End of Treatment, 26 weeks
Other outcomes:
Locations:
city: Tbilisi
country: Georgia
facility: National Center for Tuberculosis and Lung Diseases
city: Chisinau
country: Moldova, Republic of
facility: Institute of Phthisiopneumology Chiril Draganiuc
city: Moscow
country: Russian Federation
facility: Moscow City Research and Practice Tuberculosis Treatment Centre
city: Moscow
country: Russian Federation
facility: Central TB Research Institute of the Federal Agency of Scientific Organizations Moscow
city: Moscow
country: Russian Federation
facility: National Medical Research Center of Phthisiopulmonology and Infectious Diseases
city: Saint Petersburg
country: Russian Federation
facility: FSBI "Saint-Petersburg Research Institute of Phthisiopulmonology"
city: Yekaterinburg
country: Russian Federation
facility: Ural Research Institute of Phthisiopulmonology
city: Port Elizabeth
country: South Africa
facility: Empilweni TB Hospital
state: Eastern Cape
city: Klerksdorp
country: South Africa
facility: Tshepong Hospital
state: North - West
city: Durban
country: South Africa
facility: King DinuZulu Hospital Complex
city: Johannesburg
country: South Africa
facility: Clinical HIV Research Unit (CHRU) Sizwe Tropical Diseases Hospital
Study officials:
affiliation: Isango Lethemba TB Research Unit
name: Francesca Conradie
role: PRINCIPAL_INVESTIGATOR
References:
citation: Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M; ZeNix Trial Team. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430.