HIV, Tuberculosis
Conditions
Keywords
rifapentine, clofazimine, drug-susceptible tuberculosis, tuberculosis treatment shortening
Brief summary
The purpose of this study was to compare a 3-month rifapentine (RPT)/clofazimine (CFZ)-containing regimen with a CFZ loading dose with the 6-month standard of care (SOC) regimen for drug-susceptible (DS) tuberculosis (TB).
Detailed description
This study compared a 3-month rifapentine (RPT)/clofazimine (CFZ)-containing regimen with a CFZ loading dose with the 6-month standard of care (SOC) for drug-susceptible (DS) tuberculosis (TB). Randomization was stratified based on HIV status and the presence of advanced disease as determined by chest X-ray. Participants were randomized to one of three arms: * Arm 1 (Experimental): rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + CFZ 300 mg once daily for 2 weeks; then PHZE + CFZ 100 mg once daily for 6 weeks; then rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg once daily for 5 weeks * Arm 2 (SOC): rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 weeks; then rifampicin/isoniazid (RH) for 18 weeks * Arm C (PK-only subgroup): PHZE + CFZ 100 mg once daily for 4 weeks; then remain on study, off study medications and treated according to SOC (RHZE for 4 weeks; then RH for 18 weeks) All participants received pyridoxine (vitamin B6) with each dose of isoniazid (INH) based on current local, national or international dosing guidelines. Arm 1 participants were treated for 13 weeks (including a 2-week CFZ loading dose of 300 mg daily). Arm 2 participants were treated for 26 weeks, and Arm C participants were treated for 4 weeks. All participants in Arms 1, 2, and C were followed from randomization to Week 65. On June 1, 2023, the Data and Safety Monitoring Board (DSMB) recommended that the study permanently close to accrual because of the high rate of treatment failure and TB recurrence. The A5362 team, NIAID and DAIDS leadership, and ACTG leadership concurred with the DSMB's recommendation and the study was closed to accrual on June 2, 2023. A letter of amendment was created that extended follow-up to 117 weeks for some participants in Arm 1. Due to the early close to accrual, a primary analysis report forming the basis of the primary trial manuscript used data collected at study visits up to and including the date when the last enrolled participant completed the week 26 study visit (September 25. 2023). Another final analysis was performed using data collected at study visits up to the date when the last enrolled participant completed the week 65 assessment. Study visits included physical examinations; blood, urine, and/or sputum collection; chest X-rays; and electrocardiograms (ECG).
Interventions
DRUGRifapentine
1200 mg once daily
DRUGRifampicin
600 mg once daily
DRUGIsoniazid
300 mg once daily
DRUGPyrazinamide
1000mg once daily if weight is 40 to \<55kg; 1500mg once daily if weight is 55 to \<71kg; 2000mg once if weight is ≥71kg
DRUGEthambutol
800 mg once daily if weight is 40 to \<55kg; 1200 mg once daily if weight is 55 to \<71kg; 1600mg once if weight is ≥71kg
DRUGClofazimine loading dose
300 mg once daily for 2 weeks (loading dose), then 100 mg once daily
100 mg once daily
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pulmonary TB (among participants with or without history of prior TB treatment) identified within 5 days prior to entry by: * At least one sputum specimen positive for M. tuberculosis by molecular TB assay (Xpert) or line probe assay \[LPA\]) OR * At least one sputum specimen positive (1+ or greater) for acid-fast bacilli (AFB) on smear microscopy * Note: TB diagnosis for purposes of meeting inclusion criterion can be from a study testing laboratory or from an outside laboratory, as long as it is from a sputum sample collected within 5 days prior to entry. * Pulmonary TB diagnosed without known INH resistance (e.g., by LPA or Xpert) and without known RIF resistance (e.g., by either LPA or Xpert). * Absence of HIV-1 infection, as documented by any licensed rapid HIV test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit, within 30 days prior to entry OR HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test kit at any time prior to entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load. Two or more HIV-1 RNA viral loads of \>1,000 copies/mL are also acceptable as documentation of HIV-1 infection. * For participants living with HIV, CD4+ cell count ≥100 cells/mm\^3, obtained within 30 days prior to study entry at any network-approved non-US laboratory that is Immunology Quality Assessment (IQA) certified. * For participants living with HIV must be currently receiving or planning to initiate antiretroviral therapy (ART) at or before study week 8. * A verifiable address or residence readily accessible to facilitate directly observed therapy (DOT), and willingness to inform the study team of any change of address during the treatment and follow-up period. * The following laboratory values obtained at or within 5 days prior to entry by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practice (GCLP) and participates in appropriate external quality assurance programs. * Serum or plasma alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN) * Serum or plasma total bilirubin ≤2.5 times ULN * Serum or plasma creatinine ≤2 times ULN * Serum or plasma potassium ≥3.5 mEq/L and ≤5.5 mEq/L * Absolute neutrophil count (ANC) ≥650/mm\^3 * Hemoglobin ≥7.0 g/dL * Platelet count ≥50,000/mm\^3 * For females of reproductive potential, negative serum or urine pregnancy test within 5 days prior to entry by any US clinic or laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or is using a point of care (POC)/CLIA-waived test, or at any network-approved non-US laboratory or clinic that operates in accordance with Good Clinical Laboratory Practice (GCLP) and participates in appropriate external quality assurance programs. * Female participants of reproductive potential must agree not to participate in the conception process (i.e., active attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable nonhormonal method of contraception, as listed below, while on study treatment and for 30 days after stopping study medications. * Acceptable forms of contraception include: * Condoms * Intrauterine device or intrauterine system * Cervical cap with spermicide * Diaphragm with spermicide * Note: Hormonal birth control alone is not acceptable, as it may not be sufficiently reliable in combination with RPT or RIF. * Female participants who are not of reproductive potential must have documentation of menopause (i.e., at least 1 year amenorrheic), hysterectomy, or bilateral oophorectomy or bilateral tubal ligation. * Documentation of Karnofsky performance score ≥50 within 30 days prior to entry. * Documentation of either the presence or absence of advanced disease as determined by chest X-ray within 5 days prior to entry. * Ability and willingness of participant to provide informed consent.
Exclusion criteria
* More than 5 days of treatment directed against active TB for the current TB episode preceding study entry. * Pregnant or breast-feeding. * Unable to take oral medications. * Current receipt of clofazimine or bedaquiline or known receipt of clofazamine or bedaquiline at any time in the past. * Corrected QT based on the Fridericia correction method (QTcF) interval \>450 ms for men or \>470 ms for women within 30 days prior to entry. * Weight \<30 kg. * Current or planned use within 6 months following enrollment of one or more of the following medications: HIV protease inhibitors, HIV entry and fusion inhibitors, HIV non-nucleoside reverse transcriptase inhibitors (other than EFV), elvitegravir/cobicistat, bictegravir, quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine. * Current extrapulmonary TB, in the opinion of the site investigator. * Current or history of known personal or family long QT syndrome. * Known allergy/sensitivity or any hypersensitivity to components of study TB drugs or their formulation. * Active drug, alcohol use or dependence; or mental illness (e.g., major depression) that, in the opinion of the site investigator, would interfere with adherence to study requirements. * Known history of acute intermittent porphyria. * Other medical conditions (e.g., severe uncontrolled diabetes, liver or kidney disease, blood disorders, peripheral neuritis, chronic diarrhea) in which the current clinical condition of the participant is likely to prejudice the response to, or assessment of, treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to 12 Weeks Stable Culture Conversion in Liquid Media | From Entry through Week 12 | 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. |
| Participants Experiencing Any Grade 3 or Higher Adverse Event (AE) That is at Least a One Grade Increase From Baseline Over 65 Weeks | From entry through Week 65 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Prematurely Discontinue Their Treatment Regimen Through 65 Weeks | From entry through Week 65 | Premature discontinuation is defined as discontinuation other than due to violent death, natural disaster, or administrative censoring |
| Mean QTcF | Measured at Weeks 2, 8, and 13 (end of investigational treatment) | QT interval measured as the average of three electrocardiogram (ECG) readings taken 5-10 minutes apart, corrected with Fridericia correction |
| QTcF Interval Mean Change From Baseline | Measured at baseline and Weeks 2, 8, and 13 (end of investigational treatment) | Mean change from baseline in mean QTcF at weeks 2, 8, and end of treatment (EOT) |
| Categorized QTcF | Week 2, 8, and Week 13 | Absolute QTcF was categorized as:\< 480; ≥480 ms and \<500 ms; ≥500 ms |
| Categorized Change From Baseline | Measured at Weeks 2, 8, and Week 13 | 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 |
| Time to Stable Culture Conversion in Liquid Media Through Week 65 | From entry through Week 65 | 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 to Stable Culture Conversion in Solid Media Through Week 65 | From entry through Week 65 | 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). |
| Number of Participants Achieving Stable Liquid Culture Conversion by Week 8 | From entry through Week 8 | 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 |
| Number of Participants Achieving Stable Solid Culture Conversion by Week 8 | From entry through Week 8 | 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 |
| Number of Participants With One or More Serious Adverse Events (SAEs) | From entry through Week 65 | 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. |
| Number of Participants Achieving Stable Solid Culture Conversion by Week 12 | From entry through Week 12 | 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 |
| Median Time (Days) to Positivity in Liquid Culture (MGIT) | From screening, entry, weeks 1, 2, 3, 4, 6, 8, 10, 12 | 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. |
| Proportion of Participants With Favorable Clinical/Bacteriologic Outcome (Definition A) at 65 Weeks Post-randomization | From entry through Week 65 | 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. |
| Proportion of Participants Who Have a TB Relapse, From End of Treatment Until Week 65 | From end of treatment (week 13 for Arm 1; week 26 for Arm 2) to week 65 | 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. |
| Cumulative Proportion of Participants Who Have a TB Recurrence, From End of Treatment Until Week 65 | From end of treatment (week 13 for Arm 1; week 26 for Arm 2) to week 65 | 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. |
| Pharmacokinetic Parameter for CFZ: Minimum Concentration (Cmin) | Measured at Weeks 2 and 13 | Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13. |
| Pharmacokinetic Parameter for CFZ: Maximum Concentration (Cmax) | Measured at Weeks 2 and 13 | Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13. |
| Pharmacokinetic Parameter for CFZ: Time of Cmax (Tmax) | Measured at Weeks 2 and 13 | Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13. |
| Pharmacokinetic Parameter for CFZ: Area Under the Concentration Curve (AUC0-24h) | Measured at Weeks 2 and 13 | Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13. |
| Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Entry, Weeks 8, 13, 26, and 65 | 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. |
| Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Entry, Weeks 8, 13, 26, and 65 | 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. |
| Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Entry, Weeks 8, 13, 26, and 65 | 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. |
| Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Entry, Weeks 8, 13, 26, and 65 | 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? |
| Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Entry, Weeks 8, 13, 26, and 65 | 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? |
| Change in Chest X-ray Score From Baseline to End of Treatment in Each Arm | Entry, End of Treatment (Week 13 for Arm 1 and Week 26 for Arm 2) | 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 |
| Proportion of Participants With Favorable Composite Outcome (Definition B) at 65 Weeks Post-randomization | From entry through Week 65 | 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 |
Countries
Haiti, India, Malawi, South Africa, Zimbabwe
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Experimental Participants received rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 300 mg once daily for 2 weeks; then PHZE + CFZ 100 mg once daily for 6 weeks; then rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg once daily for 5 weeks.
Rifapentine: (P) 1200 mg once daily Isoniazid: (H) 300 mg once daily Pyrazinamide: (Z) 1000mg once daily if weight is 40 to \<55kg; 1500mg once daily if weight is 55to \<71kg; 2000mg once if weight is ≥71kg Ethambutol: (E) 800 mg once daily if weight is 40 to \<55kg; 1200 mg once daily if weight is 55 to \<71kg; 1600mg once if weight is ≥71kg Clofazimine loading dose: (CFZ) 300 mg once daily for 2 weeks (loading dose), then 100 mg once daily | 58 |
| Arm 2: Standard of Care Participants received rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 weeks; then rifampicin/isoniazid (RH) for 18 weeks.
Rifampicin: (R) 600 mg once daily Isoniazid: (H) 300 mg once daily Pyrazinamide: (Z) 1000mg once daily if weight is 40 to \<55kg; 1500mg once daily if weight is 55to \<71kg; 2000mg once if weight is ≥71kg Ethambutol: (E) 800 mg once daily if weight is 40 to \<55kg; 1200 mg once daily if weight is 55 to \<71kg; 1600mg once if weight is ≥71kg | 31 |
| Arm C: PK Only Subgroup Participants received PHZE + CFZ 100 mg once daily for 4 weeks; then remained on study, and were treated with off study medications according to local SOC (RHZE for 4 weeks; then RH for 18 weeks).
Rifapentine: (P) 1200 mg once daily Isoniazid: (H) 300 mg once daily Pyrazinamide: (Z) 1000mg once daily if weight is 40 to \<55kg; 1500mg once daily if weight is 55to \<71kg; 2000mg once if weight is ≥71kg Ethambutol: (E) 800 mg once daily if weight is 40 to \<55kg; 1200 mg once daily if weight is 55 to \<71kg; 1600mg once if weight is ≥71kg Clofazimine: (CFZ) 100 mg once daily | 15 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 1 |
| Overall Study | DSMB Mandated Extension of follow-up | 29 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 3 | 0 |
| Overall Study | Participant is in prison | 1 | 0 | 0 |
| Overall Study | Participant moved out of country | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Arm 1: Experimental | Arm 2: Standard of Care | Arm C: PK Only Subgroup | Total |
|---|---|---|---|---|
| Age, Continuous | 33 years | 30 years | 35 years | 33 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 26 Participants | 15 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 5 Participants | 0 Participants | 14 Participants |
| Race/Ethnicity, Customized ASIAN | 9 Participants | 6 Participants | 0 Participants | 15 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 49 Participants | 25 Participants | 15 Participants | 89 Participants |
| Region of Enrollment Haiti | 2 participants | 2 participants | 0 participants | 4 participants |
| Region of Enrollment India | 9 participants | 5 participants | 0 participants | 14 participants |
| Region of Enrollment Malawi | 26 participants | 11 participants | 9 participants | 46 participants |
| Region of Enrollment South Africa | 11 participants | 6 participants | 3 participants | 20 participants |
| Region of Enrollment Zimbabwe | 10 participants | 7 participants | 3 participants | 20 participants |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 2 Participants | 22 Participants |
| Sex: Female, Male Male | 47 Participants | 22 Participants | 13 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 58 | 1 / 31 | 1 / 15 |
| other Total, other adverse events | 25 / 58 | 7 / 31 | 3 / 15 |
| serious Total, serious adverse events | 8 / 58 | 2 / 31 | 2 / 15 |
Outcome results
Primary
Participants Experiencing Any Grade 3 or Higher Adverse Event (AE) That is at Least a One Grade Increase From Baseline Over 65 Weeks
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
Time frame: From entry through Week 65
Population: Safety set: All participants who started assigned study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: Experimental | Participants Experiencing Any Grade 3 or Higher Adverse Event (AE) That is at Least a One Grade Increase From Baseline Over 65 Weeks | Number of Participants through Primary Manuscript Cutoff date of September 25, 2023 | 26 Participants |
| Arm 1: Experimental | Participants Experiencing Any Grade 3 or Higher Adverse Event (AE) That is at Least a One Grade Increase From Baseline Over 65 Weeks | Number of Participants through Week 65 | 27 Participants |
| Arm 2: Standard of Care | Participants Experiencing Any Grade 3 or Higher Adverse Event (AE) That is at Least a One Grade Increase From Baseline Over 65 Weeks | Number of Participants through Primary Manuscript Cutoff date of September 25, 2023 | 5 Participants |
| Arm 2: Standard of Care | Participants Experiencing Any Grade 3 or Higher Adverse Event (AE) That is at Least a One Grade Increase From Baseline Over 65 Weeks | Number of Participants through Week 65 | 6 Participants |
| Arm C: PK Only Subgroup | Participants Experiencing Any Grade 3 or Higher Adverse Event (AE) That is at Least a One Grade Increase From Baseline Over 65 Weeks | Number of Participants through Primary Manuscript Cutoff date of September 25, 2023 | 3 Participants |
| Arm C: PK Only Subgroup | Participants Experiencing Any Grade 3 or Higher Adverse Event (AE) That is at Least a One Grade Increase From Baseline Over 65 Weeks | Number of Participants through Week 65 | 3 Participants |
Comparison: The point estimate and 90% two-sided confidence intervals for the difference in cumulative proportions of participants experiencing a Grade 3 or higher AE that is at least one-grade increase from baseline at any time during the 65-week study period was compared between Arm 1 and Arm 2.~This outcome measure is limited to data obtained up to September 25, 2023.p-value: <0.0190% CI: [0.14, 0.45]Wald chi-square test
Comparison: The point estimate and 90% two-sided confidence intervals for the difference in cumulative proportions of participants experiencing a Grade 3 or higher AE that is at least one-grade increase from baseline at any time during the 65-week study period was compared between Arm 1 and Arm 2.~All data through week 65.p-value: <0.0190% CI: [0.11, 0.44]Wald chi-square test
Primary
Time to 12 Weeks Stable Culture Conversion in Liquid Media
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.
Time frame: From Entry through Week 12
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Experimental | Time to 12 Weeks Stable Culture Conversion in Liquid Media | 6 weeks |
| Arm 2: Standard of Care | Time to 12 Weeks Stable Culture Conversion in Liquid Media | 8 weeks |
Comparison: This comparison is adjusting for HIV-1 status (positive/negative) and TB Disease at Screening (Advanced/Not Advanced).p-value: 0.2190% CI: [0.82, 1.79]Regression, Cox
Secondary
Categorized Change From Baseline
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
Time frame: Measured at Weeks 2, 8, and Week 13
Population: Limited to the safety analysis set, participants who started assigned treatment, in Arm 1 and Arm 2 and with available data.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Arm 1: Experimental | Categorized Change From Baseline | Week 2 | QTcF change from baseline of ≥60 ms | 2 Participants |
| Arm 1: Experimental | Categorized Change From Baseline | Week 8 | QTcF change from baseline of <30 ms | 36 Participants |
| Arm 1: Experimental | Categorized Change From Baseline | Week 8 | QTcF change from baseline of ≥30 ms and <60 ms | 17 Participants |
| Arm 1: Experimental | Categorized Change From Baseline | Week 13 | QTcF change from baseline of ≥30 ms and <60 ms | 22 Participants |
| Arm 1: Experimental | Categorized Change From Baseline | Week 2 | QTcF change from baseline of <30 ms | 39 Participants |
| Arm 1: Experimental | Categorized Change From Baseline | Week 13 | QTcF change from baseline of ≥60 ms | 5 Participants |
| Arm 1: Experimental | Categorized Change From Baseline | Week 8 | QTcF change from baseline of ≥60 ms | 1 Participants |
| Arm 1: Experimental | Categorized Change From Baseline | Week 13 | QTcF change from baseline of <30 ms | 28 Participants |
| Arm 1: Experimental | Categorized Change From Baseline | Week 2 | QTcF change from baseline of ≥30 ms and <60 ms | 15 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 13 | QTcF change from baseline of <30 ms | 27 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 2 | QTcF change from baseline of ≥30 ms and <60 ms | 1 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 2 | QTcF change from baseline of ≥60 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 2 | QTcF change from baseline of <30 ms | 28 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 8 | QTcF change from baseline of ≥30 ms and <60 ms | 2 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 8 | QTcF change from baseline of ≥60 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 8 | QTcF change from baseline of <30 ms | 29 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 13 | QTcF change from baseline of ≥30 ms and <60 ms | 3 Participants |
| Arm 2: Standard of Care | Categorized Change From Baseline | Week 13 | QTcF change from baseline of ≥60 ms | 0 Participants |
Comparison: Compares the odds of participants having maximum occurrence of QTcF change from baseline of ≥30 ms and \<60 ms, or ≥60 ms between Arm 1 and Arm 2 in the safety set using the proportional odds model.p-value: <0.0195% CI: [2.4, 21.3]Regression, Logistic
Comparison: Proportion of Participants with Worst Changes in QTcF from Screening \>= 30 ms over visits at Weeks 2, 8, 13p-value: <0.0195% CI: [0.17, 0.58]exact unconditional
Secondary
Categorized QTcF
Absolute QTcF was categorized as:\< 480; ≥480 ms and \<500 ms; ≥500 ms
Time frame: Week 2, 8, and Week 13
Population: Safety set: participants who started Arm 1 and Arm 2 and with data available.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Arm 1: Experimental | Categorized QTcF | Week 2 | Absolute QTcF ≥500 ms | 0 Participants |
| Arm 1: Experimental | Categorized QTcF | Week 8 | Absolute QTcF < 480 ms | 54 Participants |
| Arm 1: Experimental | Categorized QTcF | Week 2 | Absolute QTcF ≥480 ms and <500 ms | 0 Participants |
| Arm 1: Experimental | Categorized QTcF | Week 13 | Absolute QTcF ≥480 ms and <500 ms | 0 Participants |
| Arm 1: Experimental | Categorized QTcF | Week 8 | Absolute QTcF ≥480 ms and <500 ms | 0 Participants |
| Arm 1: Experimental | Categorized QTcF | Week 13 | Absolute QTcF ≥500 ms | 0 Participants |
| Arm 1: Experimental | Categorized QTcF | Week 2 | Absolute QTcF < 480 ms | 56 Participants |
| Arm 1: Experimental | Categorized QTcF | Week 13 | Absolute QTcF < 480 ms | 55 Participants |
| Arm 1: Experimental | Categorized QTcF | Week 8 | Absolute QTcF ≥500 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 13 | Absolute QTcF < 480 ms | 30 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 2 | Absolute QTcF ≥480 ms and <500 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 2 | Absolute QTcF ≥500 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 8 | Absolute QTcF ≥480 ms and <500 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 8 | Absolute QTcF ≥500 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 8 | Absolute QTcF < 480 ms | 31 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 13 | Absolute QTcF ≥480 ms and <500 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 13 | Absolute QTcF ≥500 ms | 0 Participants |
| Arm 2: Standard of Care | Categorized QTcF | Week 2 | Absolute QTcF < 480 ms | 29 Participants |
Secondary
Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation
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?
Time frame: Entry, Weeks 8, 13, 26, and 65
Population: Participants in Arm 1 and Arm 2 with follow-up after week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 8 | 1.60 score on a scale | Standard Deviation 2.65 |
| Arm 1: Experimental | Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 13 | 2.15 score on a scale | Standard Deviation 2.65 |
| Arm 1: Experimental | Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 26 | 0.53 score on a scale | Standard Deviation 1.41 |
| Arm 1: Experimental | Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 65 | 0.25 score on a scale | Standard Deviation 1.6 |
| Arm 2: Standard of Care | Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 65 | 0.38 score on a scale | Standard Deviation 1.68 |
| Arm 2: Standard of Care | Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 8 | 0.53 score on a scale | Standard Deviation 1.11 |
| Arm 2: Standard of Care | Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 26 | 0.79 score on a scale | Standard Deviation 1.95 |
| Arm 2: Standard of Care | Change From Baseline in Participant-reported Changes in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 13 | 0.17 score on a scale | Standard Deviation 0.54 |
Secondary
Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation
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?
Time frame: Entry, Weeks 8, 13, 26, and 65
Population: Participants in Arm 1 and Arm 2 with follow-up after week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 8 | 1.02 score on a scale | Standard Deviation 2.48 |
| Arm 1: Experimental | Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 13 | 0.89 score on a scale | Standard Deviation 2.01 |
| Arm 1: Experimental | Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 26 | 0.21 score on a scale | Standard Deviation 1.52 |
| Arm 1: Experimental | Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 65 | 0.21 score on a scale | Standard Deviation 1.7 |
| Arm 2: Standard of Care | Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 65 | 0.15 score on a scale | Standard Deviation 0.88 |
| Arm 2: Standard of Care | Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 8 | 0.17 score on a scale | Standard Deviation 0.75 |
| Arm 2: Standard of Care | Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 26 | 0.07 score on a scale | Standard Deviation 0.8 |
| Arm 2: Standard of Care | Change From Baseline in Participant-reported Distress Caused by Change in Skin Pigment Related to Perceived Skin Hyperpigmentation | Week 13 | -0.07 score on a scale | Standard Deviation 0.26 |
Secondary
Change in Chest X-ray Score From Baseline to End of Treatment in Each Arm
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
Time frame: Entry, End of Treatment (Week 13 for Arm 1 and Week 26 for Arm 2)
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions and had data available at both time points.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1: Experimental | Change in Chest X-ray Score From Baseline to End of Treatment in Each Arm | -25.51 score on a scale |
| Arm 2: Standard of Care | Change in Chest X-ray Score From Baseline to End of Treatment in Each Arm | -46.10 score on a scale |
Comparison: This comparison is adjusting for HIV-1 status (positive/negative) and TB Disease at Screening (Advanced/Not Advanced).p-value: <0.0195% CI: [5.71, 35.16]Regression, Linear
Secondary
Cumulative Proportion of Participants Who Have a TB Recurrence, From End of Treatment Until Week 65
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.
Time frame: From end of treatment (week 13 for Arm 1; week 26 for Arm 2) to week 65
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions and at risk for TB Recurrence
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Experimental | Cumulative Proportion of Participants Who Have a TB Recurrence, From End of Treatment Until Week 65 | Within 26 Weeks of Treatment Completion | 0.21 proportion of participants |
| Arm 1: Experimental | Cumulative Proportion of Participants Who Have a TB Recurrence, From End of Treatment Until Week 65 | Within 39 Weeks of Treatment Completion | 0.23 proportion of participants |
| Arm 1: Experimental | Cumulative Proportion of Participants Who Have a TB Recurrence, From End of Treatment Until Week 65 | Within 52Weeks of Treatment Completion | 0.23 proportion of participants |
| Arm 2: Standard of Care | Cumulative Proportion of Participants Who Have a TB Recurrence, From End of Treatment Until Week 65 | Within 26 Weeks of Treatment Completion | 0.04 proportion of participants |
| Arm 2: Standard of Care | Cumulative Proportion of Participants Who Have a TB Recurrence, From End of Treatment Until Week 65 | Within 39 Weeks of Treatment Completion | 0.04 proportion of participants |
Secondary
Mean Change From Baseline in Skin Pigmentation (Colorimetric a*)
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.
Time frame: Entry, Weeks 8, 13, 26, and 65
Population: Limited to the safety analysis set, participants who started assigned treatment, and were not premature study discontinuations before week 8 and had data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Inner Arm - Week 8 | 0.23 units on a scale | Standard Deviation 5.86 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Inner Arm - Week 13 | 2.14 units on a scale | Standard Deviation 8.61 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Inner Arm - Week 26 | -1.09 units on a scale | Standard Deviation 5.72 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Inner Arm - Week 65 | -0.96 units on a scale | Standard Deviation 5.51 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Face - Week 8 | -0.58 units on a scale | Standard Deviation 1.86 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Face - Week 13 | -0.46 units on a scale | Standard Deviation 2.99 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Face - Week 26 | -0.66 units on a scale | Standard Deviation 1.71 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Face - Week 65 | -0.23 units on a scale | Standard Deviation 2.2 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Face - Week 65 | 0.23 units on a scale | Standard Deviation 2.01 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Inner Arm - Week 8 | .20 units on a scale | Standard Deviation 2.44 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Face - Week 8 | -0.09 units on a scale | Standard Deviation 3.77 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Inner Arm - Week 13 | -0.34 units on a scale | Standard Deviation 6.4 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Face - Week 26 | -0.43 units on a scale | Standard Deviation 1.56 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Inner Arm - Week 26 | -1.01 units on a scale | Standard Deviation 4.97 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Face - Week 13 | -0.28 units on a scale | Standard Deviation 1.19 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric a*) | Inner Arm - Week 65 | -1.37 units on a scale | Standard Deviation 5.96 |
Secondary
Mean Change From Baseline in Skin Pigmentation (Colorimetric b*)
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.
Time frame: Entry, Weeks 8, 13, 26, and 65
Population: Limited to the safety analysis set, participants who started assigned treatment, and were not premature study discontinuations before week 8 and had data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Inner Arm - Week 8 | -1.62 units on a scale | Standard Deviation 3.49 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Inner Arm - Week 13 | -2.27 units on a scale | Standard Deviation 3.38 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Inner Arm - Week 26 | -1.52 units on a scale | Standard Deviation 4.5 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Inner Arm - Week 65 | -1.70 units on a scale | Standard Deviation 3.37 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Face - Week 8 | -2.48 units on a scale | Standard Deviation 2.15 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Face - Week 13 | -2.65 units on a scale | Standard Deviation 2.75 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Face - Week 26 | -2.44 units on a scale | Standard Deviation 2.89 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Face - Week 65 | -1.72 units on a scale | Standard Deviation 2.52 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Face - Week 65 | -0.88 units on a scale | Standard Deviation 2.17 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Inner Arm - Week 8 | -1.21 units on a scale | Standard Deviation 3.07 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Face - Week 8 | -0.82 units on a scale | Standard Deviation 2.97 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Inner Arm - Week 13 | 0.11 units on a scale | Standard Deviation 4.28 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Face - Week 26 | -0.92 units on a scale | Standard Deviation 2.55 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Inner Arm - Week 26 | -0.71 units on a scale | Standard Deviation 3.86 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Face - Week 13 | -0.66 units on a scale | Standard Deviation 2.44 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric b*) | Inner Arm - Week 65 | -1.29 units on a scale | Standard Deviation 4.06 |
Secondary
Mean Change From Baseline in Skin Pigmentation (Colorimetric L*)
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.
Time frame: Entry, Weeks 8, 13, 26, and 65
Population: Limited to the safety analysis set, participants who started assigned treatment, and were not premature study discontinuations before week 8 and had data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Inner Arm - Week 8 | -2.54 units on a scale | Standard Deviation 2.51 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Inner Arm - Week 13 | -4.72 units on a scale | Standard Deviation 3.1 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Inner Arm - Week 26 | -2.8 units on a scale | Standard Deviation 3 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Inner Arm - Week 65 | -1.15 units on a scale | Standard Deviation 3.45 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Face - Week 8 | -3 units on a scale | Standard Deviation 2.3 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Face - Week 13 | -3.61 units on a scale | Standard Deviation 2.86 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Face - Week 26 | -2.65 units on a scale | Standard Deviation 2.5 |
| Arm 1: Experimental | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Face - Week 65 | -0.45 units on a scale | Standard Deviation 2.96 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Face - Week 65 | 0.34 units on a scale | Standard Deviation 2.31 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Inner Arm - Week 8 | -1.65 units on a scale | Standard Deviation 2.17 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Face - Week 8 | -0.96 units on a scale | Standard Deviation 2.16 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Inner Arm - Week 13 | 0.02 units on a scale | Standard Deviation 2.74 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Face - Week 26 | -0.43 units on a scale | Standard Deviation 2.16 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Inner Arm - Week 26 | -0.68 units on a scale | Standard Deviation 2.54 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Face - Week 13 | -0.51 units on a scale | Standard Deviation 1.97 |
| Arm 2: Standard of Care | Mean Change From Baseline in Skin Pigmentation (Colorimetric L*) | Inner Arm - Week 65 | 1.19 units on a scale | Standard Deviation 3.52 |
Secondary
Mean QTcF
QT interval measured as the average of three electrocardiogram (ECG) readings taken 5-10 minutes apart, corrected with Fridericia correction
Time frame: Measured at Weeks 2, 8, and 13 (end of investigational treatment)
Population: Limited to available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Mean QTcF | Mean QTcF Interval at Week 2 | 419 ms | Standard Deviation 19.4 |
| Arm 1: Experimental | Mean QTcF | Mean QTcF Interval at Week 8 | 422 ms | Standard Deviation 16.8 |
| Arm 1: Experimental | Mean QTcF | Mean QTcF Interval at Week 13 | 427 ms | Standard Deviation 19.5 |
| Arm 2: Standard of Care | Mean QTcF | Mean QTcF Interval at Week 2 | 401 ms | Standard Deviation 14.8 |
| Arm 2: Standard of Care | Mean QTcF | Mean QTcF Interval at Week 8 | 408 ms | Standard Deviation 16.8 |
| Arm 2: Standard of Care | Mean QTcF | Mean QTcF Interval at Week 13 | 407 ms | Standard Deviation 20.4 |
Secondary
Median Time (Days) to Positivity in Liquid Culture (MGIT)
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.
Time frame: From screening, entry, weeks 1, 2, 3, 4, 6, 8, 10, 12
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions with data available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 6 Time to Positivity | 42 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 2 Time to Positivity | 16.8 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 8 Time to Positivity | 42 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Entry Time to Positivity | 8.63 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 10 Time to Positivity | 42 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 3 Time to Positivity | 20.2 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 12 Time to Positivity | 42 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Screening Time to Positivity | 6.17 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 4 Time to Positivity | 25.1 days |
| Arm 1: Experimental | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 1 Time to Positivity | 12.8 days |
| Arm 2: Standard of Care | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 12 Time to Positivity | 42 days |
| Arm 2: Standard of Care | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Screening Time to Positivity | 5.67 days |
| Arm 2: Standard of Care | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Entry Time to Positivity | 8.23 days |
| Arm 2: Standard of Care | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 2 Time to Positivity | 12.1 days |
| Arm 2: Standard of Care | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 4 Time to Positivity | 16.5 days |
| Arm 2: Standard of Care | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 6 Time to Positivity | 42 days |
| Arm 2: Standard of Care | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 8 Time to Positivity | 42 days |
| Arm 2: Standard of Care | Median Time (Days) to Positivity in Liquid Culture (MGIT) | Week 10 Time to Positivity | 42 days |
Comparison: Time point: Screeningp-value: 0.59795% CI: [0.57, 1.39]Regression, Cox
Comparison: Time point: Entryp-value: 0.795% CI: [0.58, 1.44]Regression, Cox
Comparison: Time point: Week 2p-value: 0.0795% CI: [0.4, 1.03]Regression, Cox
Comparison: Time point: Week 4p-value: 0.0495% CI: [0.34, 0.98]Regression, Cox
Comparison: Time point: Week 6p-value: 0.695% CI: [0.41, 1.67]Regression, Cox
Comparison: Time point: Week 8p-value: 0.59595% CI: [0.33, 1.88]Regression, Cox
Comparison: Time point: Week 10p-value: 0.6695% CI: [0.25, 2.44]Regression, Cox
Comparison: Time point: Week 12p-value: 0.8695% CI: [0.21, 6.39]Regression, Cox
Secondary
Number of Participants Achieving Stable Liquid Culture Conversion by Week 8
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 frame: From entry through Week 8
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Experimental | Number of Participants Achieving Stable Liquid Culture Conversion by Week 8 | 41 Participants |
| Arm 2: Standard of Care | Number of Participants Achieving Stable Liquid Culture Conversion by Week 8 | 19 Participants |
p-value: 0.2395% CI: [-0.07, 0.35]Fisher Exact
Secondary
Number of Participants Achieving Stable Solid Culture Conversion by Week 12
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 frame: From entry through Week 12
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Experimental | Number of Participants Achieving Stable Solid Culture Conversion by Week 12 | 53 Participants |
| Arm 2: Standard of Care | Number of Participants Achieving Stable Solid Culture Conversion by Week 12 | 30 Participants |
p-value: 195% CI: [-0.1, 0.13]Fisher Exact
Secondary
Number of Participants Achieving Stable Solid Culture Conversion by Week 8
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 frame: From entry through Week 8
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Experimental | Number of Participants Achieving Stable Solid Culture Conversion by Week 8 | 47 Participants |
| Arm 2: Standard of Care | Number of Participants Achieving Stable Solid Culture Conversion by Week 8 | 25 Participants |
p-value: 0.5695% CI: [-0.11, 0.24]Fisher Exact
Secondary
Number of Participants Who Prematurely Discontinue Their Treatment Regimen Through 65 Weeks
Premature discontinuation is defined as discontinuation other than due to violent death, natural disaster, or administrative censoring
Time frame: From entry through Week 65
Population: Safety set: All participants who started assigned study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Experimental | Number of Participants Who Prematurely Discontinue Their Treatment Regimen Through 65 Weeks | 2 Participants |
| Arm 2: Standard of Care | Number of Participants Who Prematurely Discontinue Their Treatment Regimen Through 65 Weeks | 3 Participants |
p-value: 0.3595% CI: [-0.22, 0.05]Fisher Exact
Secondary
Number of Participants With One or More Serious Adverse Events (SAEs)
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.
Time frame: From entry through Week 65
Population: Safety set: All participants who started assigned study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Experimental | Number of Participants With One or More Serious Adverse Events (SAEs) | 8 Participants |
| Arm 2: Standard of Care | Number of Participants With One or More Serious Adverse Events (SAEs) | 2 Participants |
| Arm C: PK Only Subgroup | Number of Participants With One or More Serious Adverse Events (SAEs) | 2 Participants |
Comparison: The point estimate and 90% two-sided confidence intervals for the difference in cumulative proportions of participants experiencing an SAE through week 65 was compared between Arm 1 and Arm 2.p-value: 0.2790% CI: [-0.04, 0.18]Wald chi-square test
Secondary
Pharmacokinetic Parameter for CFZ: Area Under the Concentration Curve (AUC0-24h)
Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13.
Time frame: Measured at Weeks 2 and 13
Population: Intensive PK tests were performed at weeks 2 and 13 on Arm 1 participants who consent and were registered to the Intensive PK subgroup and at week 2 on Arm C participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Pharmacokinetic Parameter for CFZ: Area Under the Concentration Curve (AUC0-24h) | Week 2 | 15.6 mg/L*h | Standard Deviation 5.58 |
| Arm 1: Experimental | Pharmacokinetic Parameter for CFZ: Area Under the Concentration Curve (AUC0-24h) | Week 13 | 16.9 mg/L*h | Standard Deviation 5.57 |
| Arm 2: Standard of Care | Pharmacokinetic Parameter for CFZ: Area Under the Concentration Curve (AUC0-24h) | Week 2 | 5.42 mg/L*h | Standard Deviation 2.48 |
Secondary
Pharmacokinetic Parameter for CFZ: Maximum Concentration (Cmax)
Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13.
Time frame: Measured at Weeks 2 and 13
Population: Intensive PK tests were performed at weeks 2 and 13 on Arm 1 participants who consent and were registered to the Intensive PK subgroup and at week 2 on Arm C participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Pharmacokinetic Parameter for CFZ: Maximum Concentration (Cmax) | Week 2 | 0.861 mg/L | Standard Deviation 0.286 |
| Arm 1: Experimental | Pharmacokinetic Parameter for CFZ: Maximum Concentration (Cmax) | Week 13 | 0.819 mg/L | Standard Deviation 0.247 |
| Arm 2: Standard of Care | Pharmacokinetic Parameter for CFZ: Maximum Concentration (Cmax) | Week 2 | 0.277 mg/L | Standard Deviation 0.123 |
Secondary
Pharmacokinetic Parameter for CFZ: Minimum Concentration (Cmin)
Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13.
Time frame: Measured at Weeks 2 and 13
Population: Intensive PK tests were performed at weeks 2 and 13 on Arm 1 participants who consent and were registered to the Intensive PK subgroup and at week 2 on Arm C participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Pharmacokinetic Parameter for CFZ: Minimum Concentration (Cmin) | Week 2 | 0.473 mg/L | Standard Deviation 0.181 |
| Arm 1: Experimental | Pharmacokinetic Parameter for CFZ: Minimum Concentration (Cmin) | Week 13 | 0.594 mg/L | Standard Deviation 0.197 |
| Arm 2: Standard of Care | Pharmacokinetic Parameter for CFZ: Minimum Concentration (Cmin) | Week 2 | 0.169 mg/L | Standard Deviation 0.088 |
Secondary
Pharmacokinetic Parameter for CFZ: Time of Cmax (Tmax)
Estimated using noncompartmental methods applied to concentrations from intensive PK sampling visits at weeks 2 and 13.
Time frame: Measured at Weeks 2 and 13
Population: Intensive PK tests were performed at weeks 2 and 13 on Arm 1 participants who consent and were registered to the Intensive PK subgroup and at week 2 on Arm C participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | Pharmacokinetic Parameter for CFZ: Time of Cmax (Tmax) | Week 2 | 4.97 hours | Standard Deviation 2.1 |
| Arm 1: Experimental | Pharmacokinetic Parameter for CFZ: Time of Cmax (Tmax) | Week 13 | 7.27 hours | Standard Deviation 4.68 |
| Arm 2: Standard of Care | Pharmacokinetic Parameter for CFZ: Time of Cmax (Tmax) | Week 2 | 7.74 hours | Standard Deviation 4.9 |
Secondary
Proportion of Participants Who Have a TB Relapse, From End of Treatment Until Week 65
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.
Time frame: From end of treatment (week 13 for Arm 1; week 26 for Arm 2) to week 65
Population: No participants have results as results for whole genome sequencing, 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.
Secondary
Proportion of Participants With Favorable Clinical/Bacteriologic Outcome (Definition A) at 65 Weeks Post-randomization
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.
Time frame: From entry through Week 65
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Experimental | Proportion of Participants With Favorable Clinical/Bacteriologic Outcome (Definition A) at 65 Weeks Post-randomization | .50 proportion of participants |
| Arm 2: Standard of Care | Proportion of Participants With Favorable Clinical/Bacteriologic Outcome (Definition A) at 65 Weeks Post-randomization | .76 proportion of participants |
Comparison: The point estimate and 95% two-sided confidence interval for the difference in cumulative proportions of participants experiencing a favorable outcome through week 65 was compared between Arm 1 and Arm 2.p-value: 0.0195% CI: [-0.47, -0.06]Wald chi-square test
Secondary
Proportion of Participants With Favorable Composite Outcome (Definition B) at 65 Weeks Post-randomization
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
Time frame: From entry through Week 65
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Experimental | Proportion of Participants With Favorable Composite Outcome (Definition B) at 65 Weeks Post-randomization | 0.49 proportion of participants |
| Arm 2: Standard of Care | Proportion of Participants With Favorable Composite Outcome (Definition B) at 65 Weeks Post-randomization | 0.74 proportion of participants |
Comparison: The point estimate and 95% two-sided confidence interval for the difference in cumulative proportions of participants experiencing a favorable outcome through week 65 was compared between Arm 1 and Arm 2.p-value: 0.0295% CI: [-0.46, -0.04]Wald chi-square
Secondary
QTcF Interval Mean Change From Baseline
Mean change from baseline in mean QTcF at weeks 2, 8, and end of treatment (EOT)
Time frame: Measured at baseline and Weeks 2, 8, and 13 (end of investigational treatment)
Population: Limited to participants with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Experimental | QTcF Interval Mean Change From Baseline | Change in mean QTcF from Week 2 to Screening | 23.9 ms | Standard Deviation 21.2 |
| Arm 1: Experimental | QTcF Interval Mean Change From Baseline | Change in mean QTcF from Week 8 to Screening | 26.5 ms | Standard Deviation 20.1 |
| Arm 1: Experimental | QTcF Interval Mean Change From Baseline | Change in mean QTcF from Week 13 to Screening | 31.6 ms | Standard Deviation 20.7 |
| Arm 2: Standard of Care | QTcF Interval Mean Change From Baseline | Change in mean QTcF from Week 2 to Screening | 0.736 ms | Standard Deviation 19.8 |
| Arm 2: Standard of Care | QTcF Interval Mean Change From Baseline | Change in mean QTcF from Week 8 to Screening | 7.38 ms | Standard Deviation 14.6 |
| Arm 2: Standard of Care | QTcF Interval Mean Change From Baseline | Change in mean QTcF from Week 13 to Screening | 7.77 ms | Standard Deviation 19 |
p-value: <0.0195% CI: [15.13, 32.94]Regression, Linear
Secondary
Time to Stable Culture Conversion in Liquid Media Through Week 65
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 frame: From entry through Week 65
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Experimental | Time to Stable Culture Conversion in Liquid Media Through Week 65 | 6 weeks |
| Arm 2: Standard of Care | Time to Stable Culture Conversion in Liquid Media Through Week 65 | 8 weeks |
p-value: 0.1890% CI: [0.84, 1.8]Regression, Cox
Secondary
Time to Stable Culture Conversion in Solid Media Through Week 65
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).
Time frame: From entry through Week 65
Population: Efficacy set: All participants who were randomized to study treatment Arm 1 or Arm 2 and were not late exclusions.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Experimental | Time to Stable Culture Conversion in Solid Media Through Week 65 | 6 weeks |
| Arm 2: Standard of Care | Time to Stable Culture Conversion in Solid Media Through Week 65 | 6 weeks |
Comparison: This comparison is adjusting for HIV-1 status (positive/negative) and TB Disease at Screening (Advanced/Not Advanced).p-value: 0.2590% CI: [0.8, 1.71]Regression, Cox