Trial Outcomes & Findings for Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study (NCT NCT04311502)

Participants were enrolled from November 2021 to March 2023 in 6 sites located in Malawi (2 sites), South Africa, Zimbabwe, India, and Haiti. A screening and accrual pause was instated on April 4, 2023 and subsequently formally closed to accrual on June 2, 2023 in response to recommendations from the DSMB.

Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study

The time of stable culture conversion was the visit corresponding to the first of two consecutive negative cultures without an intervening positive, and/or visits wherein the participant was unable to produce sputum and had no signs of active TB. If a participant did not culture convert, they were censored at their last culture result (regardless of result). If a participant died before conversion they were censored at 12 weeks. Participants who were lost to follow-up prior to 12 weeks with their last culture being positive were censored at 12 weeks (i.e. assumed they did not have a culture conversion by week 12), and participants who were lost to follow-up prior to 12 weeks with their last culture being negative were censored at the last sampling visit for which they had a valid culture result.

An adverse event is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1, Corrected Version 2.1, July 2017) The primary manuscript outcome measure includes data through week 65 up to September 25, 2023

Favorable Outcome are: * liquid culture negative at week 65 * without signs or symptoms of ongoing active TB and unable to produce sputum at 65 weeks * who at the end of the follow-up period are clinically without signs/symptoms of ongoing active TB and produce a sputum specimen that is contaminated in two liquid cultures without evidence of TB Unfavorable: * Absence of cure: Having a sputum sample at or after EOT that is culture-positive (any medium) with a second positive sample obtained 4 hours following the first sample. * Death from any cause except for violent or accidental cause * Had a positive culture for Mtb when last seen * Had a treatment extension beyond nominal level due to clinically inadequate response Unevaluable are: * lost to follow-up during treatment or post-treatment with their last culture being negative for Mtb * violent or accidental death * becoming pregnant during their assigned active treatment and stop their assigned treatment.

Favorable Outcome are: Same as definition A Unfavorable: Same as definition A and: * lost to follow-up during treatment phase * failing to complete treatment * receiving any one or more of the following: extension of treatment beyond the nominal level, except to make up missed doses; re-starting treatment following \>= 30 consecutive days lost to follow-up; a change in at least one drug in treatment regimen for any reason except re-infection, pregnancy, or temporary drug challenge Unevaluable are: * lost to follow-up after treatment phase, and not assessable at the end of follow-up, with their last culture being negative for Mtb * Violent death or accidental death * Women who become pregnant during their assigned active treatment and stop their assigned treatment

Premature discontinuation is defined as discontinuation other than due to violent death, natural disaster, or administrative censoring

QT interval measured as the average of three electrocardiogram (ECG) readings taken 5-10 minutes apart, corrected with Fridericia correction

Mean change from baseline in mean QTcF at weeks 2, 8, and end of treatment (EOT)

Absolute QTcF was categorized as:\< 480; ≥480 ms and \<500 ms; ≥500 ms

Categorized change from baseline as: change from baseline of \<30 ms; change from baseline of ≥30 ms and \<60 ms; change from baseline of ≥60 ms

Defined as the first of two (consecutive or non-consecutive) negative sputum cultures without an intervening positive culture, and/or visits wherein the participant is unable to produce sputum and has no signs of active TB

The time of stable culture conversion was the visit corresponding to the first of two consecutive negative cultures without an intervening positive, and/or visits wherein the participant was unable to produce sputum and had no signs of active TB. If a participant did not culture convert, they were censored at their last culture result (regardless of result). If a participant died before conversion, the death was considered as a competing event. Participants who were lost to follow-up prior to 65 weeks with their last culture being positive were censored at 65 weeks (i.e. assumed they did not have a culture conversion by week 65), and participants who were lost to follow-up prior to 65 weeks with their last culture being negative were censored at the last sampling visit for which they had a valid culture result. Adjusted model adjusts for HIV-1 status (positive/negative) and TB Disease at Screening (Advanced/Not Advanced).

Defined as the first of two (consecutive or non-consecutive) negative sputum cultures without an intervening positive culture, and/or visits wherein the participant is unable to produce sputum and has no signs of active TB

Defined as the first of two (consecutive or non-consecutive) negative sputum cultures without an intervening positive culture, and/or visits wherein the participant is unable to produce sputum and has no signs of active TB

Cumulative proportion with at least one Serious Adverse Event (SAE) A SAE is defined as any untoward medical occurrence that: * Results in death * Is life-threatening * Requires inpatient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Is an important medical event that many not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above.

Defined as the first of two (consecutive or non-consecutive) negative sputum cultures without an intervening positive culture, and/or visits wherein the participant is unable to produce sputum and has no signs of active TB

Time (days) to positivity in liquid culture (MGIT) is defined as the number of days it takes for the culture to produce results up to a max of 42 days. For negative culture results, time to positivity is imputed as 42 days.

The chest X-ray was posterior-anterior. Extent of disease (limited to one lobe or region, unilateral, bilateral, or diffuse) and cavitation status (cavities present \[location\] or absent) was documented by validated numerical score (percent of total lung affected by any pathology + 40 if cavitation is present; 0 = No percent affected, 140 = entire lung is affected + cavitation is present) for grading chest X-ray in adult smear-positive pulmonary TB (Thorax 2010; 65(10):863-9). Analysis was conducted based on site readings of CXR

The time of relapse is defined as the time from end of treatment until the first sputum sample that is culture positive in liquid or solid media for an Mtb strain that has matching genotype with the baseline isolate (as determined by whole genome sequencing). A second positive sputum sample obtained at least 4 hours following the first sputum collection is required to confirm a relapse. If the second sputum sample was negative, this was not counted as a relapse. If a participant was lost to follow-up without a second sputum sample confirmation of relapse (including contaminated or missing), it was counted as a relapse. Whole genome sequencing of samples, which is necessary to assess TB relapse, was not performed due to lack of funding. There is no plan to test these samples in the future.

The time of recurrence is defined as the time from end of treatment until the first sputum sample that is culture positive in liquid or solid media. A second positive sputum sample obtained at least 4 hours following the first sputum collection is required to confirm a recurrence. If the second sputum sample was negative, this will not be counted as a recurrence. If a participant was lost to follow-up without a second sputum sample confirmation of recurrence (including contaminated or missing), it was counted as a recurrence. Participants at risk for recurrence where those who were stable culture conversions by end of treatment.

Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13.

Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13.

Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13.

Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13.

The median of triplicate measurements of Inner Arm, and Face (median of all measurements from the Chin, Forehead, Left Cheek, and Right Cheek). L represents lightness (0 = black, 100 = white). Further data processing removed values if one of the triplicates differed more than 5% of the median.

The median of triplicate measurements of Inner Arm, and Face (median of all measurements from the Chin, Forehead, Left Cheek, and Right Cheek). The a\* parameter represents the balance between red and green. Positive values of a\* indicate a reddish tone, while negative values indicate a greenish tone. (-128 = Green, 127 = Red). Further data processing removed values if one of the triplicates differed more than 5% of the median.

The median of triplicate measurements of Inner Arm, and Face (median of all measurements from the Chin, Forehead, Left Cheek, and Right Cheek). The b\* parameter represents the balance between yellow and blue. Positive values of b\* indicate a yellowish tone, while negative values indicate a bluish tone (-128 = Blue, 127 = Yellow). Further data processing removed values if one of the triplicates differed more than 5% of the median.

Subjective questionnaire asked the following questions : 1.) On a scale from 0 to 10: (0 being none and 10 being most significant possible) How would you rate any change in the coloration of your skin since you began TB treatment?

Subjective questionnaire asked the following questions: On a scale from 0 to 10: (0 being none and 10 being worst possible) How would you rate your distress to skin coloration changes since you began TB treatment, if any?