Trial Outcomes & Findings for Linezolid Dosing Strategies in Drug-Resistant TB (NCT NCT05007821)

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.

Linezolid Dosing Strategies in Drug-Resistant TB

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.

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.

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.

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 16, 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.

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 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 of participants with stable liquid culture conversion were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula.

The study's primary completion date corresponded to the week 26 visit. Thus, data only through week 26 were analyzed. Data from the week 38 visit will be analyzed after the study completion date.

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.

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.

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.

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.

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.

The study's primary completion date corresponded to the week 26 visit. Thus, data only through week 26 were analyzed. Data from the week 38 visit will be analyzed after the study completion date.

The study's primary completion date corresponded to the week 26 visit. Thus, data only through week 26 were analyzed. Data from the week 72 visit will be analyzed after the study completion date.

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

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 parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA).

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

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 parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA).

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

Estimated based on concentrations from intensive PK sampling times at pre-dose, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

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 parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA).

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.