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

Phase 2TerminatedNCT04311502

National Institute of Allergy and Infectious Diseases (NIAID)104 enrolled

Overview

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).

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

104

Conditions

HIV Tuberculosis

Interventions

RifapentineDRUG

1200 mg once daily

RifampicinDRUG

600 mg once daily

IsoniazidDRUG

300 mg once daily

Pyrazinamide

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (6)

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, Haiti

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, India

Malawi CRS

Lilongwe, Central Region, Malawi

Blantyre CRS

Blantyre, Malawi

Outcomes

Primary Outcomes

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

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

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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1000mg once daily if weight is 40 to \<55kg; 1500mg once daily if weight is 55 to \<71kg; 2000mg once if weight is ≥71kg

EthambutolDRUG

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 doseDRUG

300 mg once daily for 2 weeks (loading dose), then 100 mg once daily

Clofazimine 100 MGDRUG

100 mg once daily

CAPRISA eThekwini CRS

Durban, KwaZulu-Natal, South Africa

Milton Park CRS

Harare, Zimbabwe

Time frame: From entry through Week 65

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

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

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)

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)

Categorized QTcF

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

Time frame: Week 2, 8, and Week 13

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

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

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

Number of Participants Achieving Stable Liquid Culture Conversion by Week 8

Time frame: From entry through Week 8

Number of Participants Achieving Stable Solid Culture Conversion by Week 8

Time frame: From entry through Week 8

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

Number of Participants Achieving Stable Solid Culture Conversion by Week 12

Time frame: From entry through Week 12

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

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)

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

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

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

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

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

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

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

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

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

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

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