Clinical trial NCT05007821: Linezolid Dosing Strategies in Drug-Resistant TB
Official title: A Phase II, Prospective, Randomized, Multicenter Trial to Evaluate the Efficacy and Safety/Tolerability of Two Linezolid Dosing Strategies in Combination With a Short Course Regimen for the Treatment of Drug-Resistant Pulmonary Tuberculosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Tuberculosis, Multidrug-Resistant
Tuberculosis
Tuberculosis, Pulmonary
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2021-08-16
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A5356 is a phase II, prospective, randomized, two-arm, open-label, multicenter clinical trial to evaluate the anti-tuberculosis (TB) activity, safety, and tolerability of an injectable-free short course regimen for treatment of multidrug-/rifampicin-resistant (MDR-/RR-), pre-extensively drug-resistant (pre-XDR-), and extensively drug-resistant (XDR-) TB comparing two dosing strategies of linezolid (LZD) combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ).
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to evaluate the efficacy (how well the medicines work) and tolerability (whether participants stop treatment because of side effects from a drug or treatment) of an anti-TB treatment regimen that compares two doses of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). This study will also measure the level of these medicines in the participants' blood.

Detailed description: There is currently no "standard of care" or single standardized treatment regimen recommended for everyone with drug resistant-tuberculosis (DR- TB). Current DR-TB treatments may not be well tolerated and can often have side effects. There is a need to identify drugs with enough anti-TB activity (treatment against TB) and good safety profiles that can improve outcomes in the treatment of DR-TB.

The main purpose of this study is to evaluate the efficacy and tolerability of a new shorter course anti-TB treatment regimen that compares two dosing strategies of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). As a secondary aim, the study will also assess the safety (the level and type of side effects from a drug or treatment) of the combination of these drugs.

Everyone in the study will take these drugs once a day for the entire treatment period: BDQ, DLM, and CFZ. The difference between the two treatment groups in the study is in how participants will take the fourth drug: LZD. Participants in group A will take one dose of LZD once a day for the entire treatment period. Participants in group B will take a higher dose of LZD once a day for 4 weeks and then continue taking that higher dose of LZD just three times a week for the rest of the treatment period.

Eligibility criteria: Inclusion Criteria:

1. Aged greater than or equal to 18 years at screening.
2. Newly diagnosed pulmonary drug-resistant tuberculosis (DR-TB), with resistance to at least rifampicin or rifampin (which is a drug used in the therapy of tuberculosis) confirmed from a sputum specimen collected within 60 days prior to entry.
3. HIV-1 infection status documented as either absent or present.
4. For participants living with HIV, either currently on an antiretroviral therapy (ART) regimen or willing and able to start ART within 30 days after entry.
5. Efavirenz or etravirine (drugs used to treat HIV) must be discontinued prior to a participant's starting anti-TB medications. For participants on efavirenz or etravirine, they must be willing and able to discontinue these at least 7 days prior to initiating study TB medications.
6. For participants living with HIV, CD4+ cell (a type of white blood cell) count greater than or equal to 50 cells/mm3 obtained within 60 days prior to study entry.
7. For females of reproductive potential, negative serum or urine pregnancy test.
8. Females of reproductive potential who are participating in sexual activity that could lead to pregnancy must agree to use two of the following forms of birth control while receiving TB study medications and for 30 days after stopping study medications:

   * Male or female condoms
   * Diaphragm or cervical cap (with spermicide, if available)
   * Intrauterine device (IUD) or intrauterine system (IUS)
   * Hormone-based birth control (e.g., oral contraceptives, Depo-Provera, NuvaRing, implants)
9. Appropriate laboratory values as determined by the study doctor obtained within 14 days prior to entry.
10. Karnofsky performance score (an assessment tool for functional impairment) greater than or equal to 50 within 30 days prior to entry.
11. Ability and willingness of candidate and/or legal guardian/representative to provide informed consent and meet requirements for the study.
12. Chest X-ray obtained within 30 days prior to entry.

Exclusion Criteria:

1. Documentation of clinically significant (as judged by the study doctor) active infections (including HIV-related opportunistic infections) other than TB and HIV requiring treatment within 30 days prior to entry.
2. Evidence of clinically significant (as judged by the study doctor) metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric, endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) that would interfere with study medications or procedures.
3. Inability to take oral medications.
4. Suspected or documented TB involving the central nervous system, clinically significant renal TB or TB pericarditis, or current extrapulmonary TB involving other organ systems that might interfere with study medications or procedures, as judged by the study doctor.
5. Prior treatment with one or more of the study drugs at any time in the past for an episode of DR-TB that is not the qualifying episode or treatment for more than 7 cumulative days with one or more of the study drugs within 30 days prior to entry for the qualifying episode of DR-TB.
6. History of allergy or hypersensitivity to any of the study drugs or medications in the same class as the study drugs.
7. Known or suspected current alcohol and/or drug abuse that is, in the opinion of the study doctor, sufficient to compromise the safety and/or cooperation of the participant.
8. Receipt of any investigational drugs within 60 days prior to entry.
9. Known history of prolonged QT syndrome (heart rhythm condition that can potentially cause fast, chaotic heartbeats) or current prolonged QT interval on screening electrocardiogram (a medical test that detects cardiac (heart) abnormalities).
10. Known history of clinically significant cardiac arrhythmia (a condition in which the heart beats with an irregular or abnormal rhythm) requiring medication or clinically significant electrocardiogram (ECG) abnormality, in the opinion of the study doctor, within 60 days prior to entry.
11. Pregnancy or current breastfeeding, or intent to become pregnant and/or breastfeed while on study treatment.
12. Current use of monoamine oxidase inhibitors (type of medication used to treat depression) or use within 30 days prior to entry.
13. Current use of serotonergic agents including SSRI/SNRI antidepressants or prior use within 30 days prior to entry.
14. Known history of optic neuropathy (damage to the optic nerve in your eye) of any grade as diagnosed by an ophthalmologist.
15. Current peripheral neuropathy (when nerves are damaged or destroyed and can't send messages from the brain and spinal cord to the muscles, skin and other parts of the body) with severe paresthesias ("pins and needles") and/or mild weakness or worse (Grade ≥2.).
16. Weight less than 35 kg (77 lbs).
17. Currently taking other prohibited medications.

Primary outcomes:
measure: Cumulative probability of sputum culture conversion
timeFrame: Up to 26 weeks
measure: Cumulative probability of permanent discontinuation of at least one anti-TB drug due to adverse events, intolerance, or death
timeFrame: Up to 26 weeks
Secondary outcomes:
measure: Cumulative probability of sputum culture conversion
timeFrame: At week 8
measure: Cumulative probability of sputum culture conversion
timeFrame: At week 16
measure: Cumulative probability of sputum culture conversion
timeFrame: At week 26
measure: Cumulative probability of sputum culture conversion
timeFrame: At week 38
measure: Cumulative probability of permanent discontinuation of LZD due to AEs, intolerance, or death; temporary discontinuation of LZD for any reason; and dose reduction of LZD
timeFrame: Up to 26 weeks
measure: Cumulative probability of treatment-related adverse events
timeFrame: Up to 26 weeks
measure: Cumulative probability of unfavorable TB treatment outcome
timeFrame: At week 26
measure: Cumulative probability of unfavorable TB treatment outcome
timeFrame: At week 38
measure: Cumulative probability of unfavorable TB treatment outcome
timeFrame: At week 72
measure: Delamanid minimum plasma concentration (Cmin)
timeFrame: At week 4
measure: Delamanid maximum plasma concentration (Cmax)
timeFrame: At week 4
measure: Delamanid time to reach maximum plasma concentration (Tmax)
timeFrame: At week 4
measure: Delamanid area under the concentration-time curve (AUC)
timeFrame: At week 4
measure: Delamanid apparent oral clearance (CL/F)
timeFrame: At week 4
measure: Linezolid minimum plasma concentration (Cmin)
timeFrame: At week 4
measure: Linezolid maximum plasma concentration (Cmax)
timeFrame: At week 4
measure: Linezolid time to reach maximum plasma concentration (Tmax)
timeFrame: At week 4
measure: Linezolid area under the concentration-time curve (AUC)
timeFrame: At week 4
measure: Linezolid apparent oral clearance (CL/F)
timeFrame: At week 4
measure: Proportion of doses taken during the treatment period
timeFrame: Up to 26 weeks
Other outcomes:
Locations:
city: Gaborone
country: Botswana
facility: Gaborone CRS (Site ID: 12701)
state: South-East District
city: Rio De Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (Site ID: 12101)
city: Port-au-Prince
country: Haiti
facility: GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (Site ID: 31730)
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS (Site ID: 30022)
city: Lima
country: Peru
facility: Barranco CRS (Site ID: 11301)
city: Cavite
country: Philippines
facility: De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC) (Site ID: 31981)
city: Johannesburg
country: South Africa
facility: Wits Helen Joseph Hospital CRS (Wits HJH CRS) (Site ID: 11101)
state: Gauteng
city: Durban
country: South Africa
facility: Durban International CRS (Site ID: 11201)
state: Kwa Zulu Natal
city: Rustenburg
country: South Africa
facility: Rustenburg CRS (Site ID: 31684)
state: North West Province
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute (UCTLI) CRS (Site ID: 31792)
state: Western Cape Province
city: Cape Town
country: South Africa
facility: South African Tuberculosis Vaccine Initiative (SATVI) CRS (Site ID: 31793)
state: Western Cape Province
city: Pathum Wan
country: Thailand
facility: Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site ID: 31802)
state: Bangkok
city: Chiang Mai
country: Thailand
facility: Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (Site ID: 31784)
Study officials:
affiliation: The University of California, San Diego
name: Constance A. Benson
role: STUDY_CHAIR
References: