Tuberculosis, Multidrug-Resistant, Tuberculosis, Tuberculosis, Pulmonary
Conditions
Brief summary
The purpose of the study was to evaluate the efficacy (how well the medicines work) and tolerability (whether participants stop treatment because of side effects from a drug) of an anti-TB treatment regimen that compared two doses of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). This study also measured the level of LZD and BDQ in the participants' blood.
Detailed description
When the study was designed, there was currently no "standard of care" or single standardized treatment regimen recommended for everyone with drug resistant-tuberculosis (DR-TB). Current DR-TB treatments were not well tolerated and often had side effects. There was a need to identify drugs with enough anti-TB activity (treatment against TB) and good safety profiles that could improve outcomes in the treatment of DR-TB. The main purpose of this study was to evaluate the efficacy and tolerability of a new shorter course anti-TB treatment regimen that compared two dosing strategies of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). As a secondary aim, the study assessed the safety (the level and type of side effects from a drug or treatment) of the combination of these drugs. Everyone in the study took BDQ, DLM, and CFZ once a day for the entire treatment period. The difference between the two treatment groups in the study was in how participants took the fourth drug: LZD. Participants in group A took one dose of LZD once a day for the entire treatment period. Participants in group B took a higher dose of LZD once a day for 4 weeks and then took that higher dose of LZD just three times a week for the rest of the treatment period.
Interventions
DRUGLinezolid 600 mg
One 600mg tablet taken orally once daily (QD) in the morning during weeks 1-26
DRUGLinezolid 1200 mg (QD)
Two 600mg tablets taken orally once daily (QD) in the morning during weeks 1-4
DRUGLinezolid 1200 mg (TIW)
Two 600mg tablets taken orally three times per week (TIW; Mon-Wed-Fri) in the morning during weeks 5-26
Two 100mg tablets taken orally once daily in the morning during weeks 1-8
One 100mg tablet taken orally once daily in the morning during weeks 9-26
DRUGDelamanid 300 mg
Six 50mg tablets taken orally once daily in the morning during weeks 1-26
DRUGClofazimine 300 mg
Three 100mg capsules taken orally once daily in the morning during weeks 1-2
One 100mg capsule taken orally once daily in the morning during weeks 3-26
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Otsuka Pharmaceutical Development & Commercialization, Inc.
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 2. HIV-1 infection status documented as either absent or present. 3. 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. 4. 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. 5. 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. 6. For females of reproductive potential, negative serum or urine pregnancy test. 7. 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) 8. Appropriate laboratory values as determined by the study doctor obtained within 14 days prior to entry. 9. Karnofsky performance score (an assessment tool for functional impairment) greater than or equal to 50 within 30 days prior to entry. 10. Ability and willingness of candidate and/or legal guardian/representative to provide informed consent and meet requirements for the study. 11. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to 26 Weeks Stable Culture Conversion in Liquid Media | Up to 26 weeks | Time of stable liquid culture conversion was the visit corresponding to the 1st of 2 consecutive MTB-neg cultures obtained at least 7 days apart without an intervening MTB-pos culture. Inability to produce sputum with or without induction was considered an MTB-neg culture. A participant was MTB-pos at a visit if at least 1 of the liquid cultures was MTB-pos. A participant was MTB-neg at a visit if both liquid cultures were MTB-neg or if 1 liquid culture was MTB-neg and the other was missing or indeterminate. If the 1st MTB-neg liquid culture was at week 26, then conversion was met. If a participant did not convert by week 26, they were censored at their last culture result. If a participant died (any cause except trauma), they were censored at week 26 (worst possible outcome). Within-arm Kaplan-Meier estimates of proportions at week 26 and the Cox proportional hazards regression model hazard ratio were calculated; between-arm differences were tested with the log rank test. |
| Proportion of Participants With Permanent Discontinuation of At Least One Anti-TB Drug Due To Adverse Events, Intolerance, Or Death | Up to 26 weeks | Time of permanent discontinuation of at least one anti-TB drug due to side effects that did not lead to a protocol-required discontinuation, due to participant non-compliance with at least one anti-TB drug or study visits, or due to participant request was the corresponding date of discontinuation. If a participant did not permanently discontinue at least one anti-TB drug due to side effects that did not lead to a protocol-required discontinuation, due to participant non-compliance with at least one anti-TB drug or study visits, or due to participant request by week 26, they were censored at the date of permanent treatment discontinuation of all study drugs or, if still on study treatment, at week 26. Within-arm Kaplan-Meier estimates of proportions of participants with permanent discontinuation were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving Stable Liquid Culture Conversion | At week 8 | Time of stable liquid culture conversion was the visit corresponding to the 1st of 2 consecutive MTB-neg cultures obtained at least 7 days apart without an intervening MTB-pos culture. Inability to produce sputum with or without induction was considered an MTB-neg culture. A participant was MTB-pos at a visit if at least 1 of the liquid cultures was MTB-pos. A participant was MTB-neg at a visit if both liquid cultures were MTB-neg or if 1 liquid culture was MTB-neg and the other was missing or indeterminate. If a participant did not convert by week 8, they were censored at their last culture result. If a participant died (any cause except trauma), they were censored at week 26 (worst possible outcome). Within-arm Kaplan-Meier estimates of proportions of participants with stable liquid culture conversion were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula. |
| Proportion of Participants With Permanent Discontinuation of LZD Due To Adverse Events, Intolerance, or Death | Up to 26 weeks | Time of permanent discontinuation of LZD due to side effects that did not lead to a protocol-required discontinuation, due to participant non-compliance with LZD or study visits, or due to participant request was the corresponding date of discontinuation. If a participant did not permanently discontinue LZD due to side effects that did not lead to a protocol-required discontinuation, due to participant non-compliance with LZD or study visits, or due to participant request by week 26, they were censored at the date of permanent discontinuation of LZD or, if still on study treatment, at week 26. Within-arm Kaplan-Meier estimates of proportions of participants with permanent discontinuation were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula. |
| Proportion of Participants With Temporary Discontinuation of LZD For Any Reason | Up to 26 weeks | Time of temporary discontinuation of LZD for any reason was the corresponding date of first temporary discontinuation. If a participant did not temporarily discontinue LZD by week 26, they were censored at the date of permanent discontinuation of LZD or, if still on study treatment, at week 26. Within-arm Kaplan-Meier estimates of proportions of participants with temporary discontinuation of LZD were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula. |
| Proportion of Participants With LZD Dose Reduction | Up to 26 weeks | Time of LZD dose reduction was the corresponding date of the first LZD dose reduction. If a participant did not undergo a LZD dose reduction by week 26, they were censored at the date of permanent discontinuation of LZD or, if still on study treatment, at week 26. Within-arm Kaplan-Meier estimates of proportions of participants with LZD dose reduction were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula. |
| Proportion of Participants With Treatment-Related Adverse Events | Up to 26 weeks | Time of treatment-related adverse event was the corresponding date of the averse event. If a participant did not experience a treatment-related adverse event, they were censored at the date of permanent treatment discontinuation of all study drugs or, if still on study treatment, at week 26. Within-arm Kaplan-Meier estimates of proportions of participants with treatment-related adverse event were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula. |
| Proportion of Participants With Unfavorable TB Treatment Outcome | At week 26 | Unfavorable TB treatment outcome is defined as meeting one or more of the following: 1. Participants with confirmed microbiologic TB treatment failure; 2. Participants who fail to complete study treatment or require extension of study treatment beyond the study-prescribed treatment duration due to clinically inadequate response; 3. Participants who had a positive sputum MTB culture at their last study visit; 4. Participants who die from any cause during study treatment, except from violent or accidental cause; or 5. Participants failing to complete study treatment and not assessable at the end of the follow-up period. If a participant did not experience an unfavorable TB treatment outcome by week 26, they were censored at their last TB treatment outcome determination. Within-arm Kaplan-Meier estimates of proportions of participants with unfavorable TB treatment outcome were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula. |
| Pharmacokinetic Parameter for Linezolid: Minimum Plasma Concentration (Cmin) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Linezolid: Maximum Plasma Concentration (Cmax) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Linezolid: Time to Reach Maximum Plasma Concentration (Tmax) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Linezolid: Area Under the Concentration-time Curve (AUC) | At week 4 | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). AUC24h (area under the curve from 0 to 24 hours) were determined using the linear-log trapezoidal rule. |
| Pharmacokinetic Parameter for Linezolid: Apparent Oral Clearance (CL/F) | At week 4 | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). |
| Pharmacokinetic Parameter for Delamanid: Minimum Plasma Concentration (Cmin) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Delamanid: Maximum Plasma Concentration (Cmax) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Delamanid: Time to Reach Maximum Plasma Concentration (Tmax) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Delamanid: Area Under the Concentration-time Curve (AUC) | At week 4 | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). AUC24h (area under the curve from 0 to 24 hours) were determined using the linear-log trapezoidal rule. |
| Pharmacokinetic Parameter for Delamanid: Apparent Oral Clearance (CL/F) | At week 4 | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). |
| Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Minimum Plasma Concentration (Cmin) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Maximum Plasma Concentration (Cmax) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Time to Reach Maximum Plasma Concentration (Tmax) | At week 4 | Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. |
| Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Area Under the Concentration-time Curve (AUC) | At week 4 | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). AUC24h (area under the curve from 0 to 24 hours) were determined using the linear-log trapezoidal rule. |
| Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Apparent Oral Clearance (CL/F) | At week 4 | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). |
| Number of Participants With >90% Directly Observed Therapy Doses Taken During the Treatment Period | Up to 26 weeks | At each visit, the site reported the number of directly observed therapy (DOT) doses since the last visit. The number of expected DOT doses was 182. The number of expected DOT doses was adjusted by removing the number of days during temporary holds due to adverse events. This avoided penalizing participants who missed DOT doses due to protocol-required treatment holds for adverse events. Participants who missed DOT doses for other reasons were penalized even if they made up the missed doses by the week 30 study visit as allowed by the protocol. The proportion of expected 182 DOT doses was calculated as the total number of DOT doses reported by the site divided by the adjusted number of expected DOT doses. |
Countries
Botswana, Brazil, Haiti, Peru, Philippines, South Africa, Thailand
Contacts
STUDY_CHAIRConstance A. Benson
The University of California, San Diego
Participant flow
Recruitment details
Participants were enrolled from 27 September 2022 to 04 September 2024 in 13 sites located in South Africa (5 sites), Haiti (2 sites), Thailand (2 sites), Botswana, Brazil, Peru, and Philippines.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 36 years STANDARD_DEVIATION 13 |
| Age, Customized Age category 18 - <30 | 54 Participants |
| Age, Customized Age category 30 - < 60 | 76 Participants |
| Age, Customized Age category >= 60 | 8 Participants |
| MTB Culture Result Indeterminate | 1 Participants |
| MTB Culture Result MTB-Negative | 14 Participants |
| MTB Culture Result MTB-Positive | 123 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 18 Participants |
| Race (NIH/OMB) Black or African American | 83 Participants |
| Race (NIH/OMB) More than one race | 16 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment Botswana | 3 participants |
| Region of Enrollment Brazil | 6 participants |
| Region of Enrollment Haiti | 4 participants |
| Region of Enrollment Peru | 5 participants |
| Region of Enrollment Philippines | 27 participants |
| Region of Enrollment South Africa | 68 participants |
| Region of Enrollment Thailand | 5 participants |
| Sex: Female, Male Female | 51 Participants |
| Sex: Female, Male Male | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 69 | 2 / 69 |
| other Total, other adverse events | 52 / 69 | 57 / 69 |
| serious Total, serious adverse events | 14 / 69 | 18 / 69 |
Outcome results
None listed