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

Study Overview
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Brief Summary
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The purpose of this study is to compare a 3-month rifapentine (RPT)/clofazimine (CFZ)-containing regimen with CFZ loading dose versus 6-month standard of care (SOC) for drug-susceptible (DS) tuberculosis (TB).

Detailed Description
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This study will compare a 3-month rifapentine (RPT)/clofazimine (CFZ)-containing regimen with CFZ loading dose versus 6-month standard of care (SOC) for drug-susceptible (DS) tuberculosis (TB). Randomization will be stratified based on HIV status and the presence of advanced disease as determined by chest X-ray. Participants will be 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 (Pharmacokinetic [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 must receive pyridoxine (vitamin B6) with each dose of isoniazid (INH) based on current local, national or international dosing guidelines. Arm 1 participants will be treated for 13 weeks (including a 2-week CFZ loading dose of 300 mg daily). Arm 2 participants will be treated for 26 weeks, and Arm C participants will be treated for 4 weeks. All participants in Arms 1, 2, and C will be followed from randomization to Week 65. Study visits may include physical examinations; blood, urine, and/or sputum collection; chest X-rays; and electrocardiograms (ECG).

Official Title
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A Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study

Conditions
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HIV, Tuberculosis

Intervention / Treatment
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* Drug: Clofazimine (CFZ)
* Drug: Rifapentine (RPT)
* Drug: Isoniazid (INH)
* Drug: Pyrazinamide (PZA)
* Drug: Ethambutol (EMB)
* Drug: Rifampicin (RIF)
* Dietary Supplement: Pyridoxine (vitamin B6)


Participation Criteria
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Eligibility Criteria
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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) and without known RIF resistance (e.g., by either LPA or Xpert). Aged ≥18 years. 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, 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Experimental 3-month, with CFZ loading dose<br>Participants will receive 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. | Drug: Clofazimine (CFZ)<br>* Administered orally once daily<br>Drug: Rifapentine (RPT)<br>* Administered orally once daily<br>Drug: Isoniazid (INH)<br>* Administered orally once daily<br>Drug: Pyrazinamide (PZA)<br>* Administered based on weight orally once daily<br>Drug: Ethambutol (EMB)<br>* Administered based on weight orally once daily<br>Dietary Supplement: Pyridoxine (vitamin B6)<br>* All participants must receive pyridoxine (vitamin B6) with each dose of INH based on current local, national or international dosing guidelines. Pyridoxine is not provided by the study.<br>|
| Active Comparator: Arm 2: Standard of care for drug-susceptible (DS) TB<br>Participants will receive rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 weeks; then rifampicin/isoniazid (RH) for 18 weeks. | Drug: Isoniazid (INH)<br>* Administered orally once daily<br>Drug: Pyrazinamide (PZA)<br>* Administered based on weight orally once daily<br>Drug: Ethambutol (EMB)<br>* Administered based on weight orally once daily<br>Drug: Rifampicin (RIF)<br>* Administered orally once daily<br>Dietary Supplement: Pyridoxine (vitamin B6)<br>* All participants must receive pyridoxine (vitamin B6) with each dose of INH based on current local, national or international dosing guidelines. Pyridoxine is not provided by the study.<br>|
| Experimental: Arm C: PK only subgroup<br>Participants will receive PHZE + CFZ 100 mg once daily for 4 weeks; then on study, off study medications and treated according to SOC (RHZE for 4 weeks; then RH for 18 weeks). | Drug: Clofazimine (CFZ)<br>* Administered orally once daily<br>Drug: Rifapentine (RPT)<br>* Administered orally once daily<br>Drug: Isoniazid (INH)<br>* Administered orally once daily<br>Drug: Pyrazinamide (PZA)<br>* Administered based on weight orally once daily<br>Drug: Ethambutol (EMB)<br>* Administered based on weight orally once daily<br>Drug: Rifampicin (RIF)<br>* Administered orally once daily<br>Dietary Supplement: Pyridoxine (vitamin B6)<br>* All participants must receive pyridoxine (vitamin B6) with each dose of INH based on current local, national or international dosing guidelines. Pyridoxine is not provided by the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to stable culture conversion in liquid media | 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 | Measured through Week 12 | 
| Proportion of participants across study arms experiencing any Grade 3 or higher adverse event (AE) that is at least a one grade increase from baseline | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, July 2017 | Measured through Week 65 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with favorable clinical/bacteriologic outcome |  | Measured at Week 65 | 
| Proportion of participants with favorable composite outcome including treatment completion |  | Measured at Week 65 | 
| Proportion of participants across study arms who prematurely discontinue their treatment regimen | Defined as discontinuation other than due to violent death, natural disaster, or administrative censoring | Measured through Week 65 | 
| Mean QTcF change from baseline |  | Measured at Weeks 2, 8, and 13 (end of investigational treatment) | 
| Occurrence of absolute QTcF ≥480 ms and ≤500 ms, and ≥500 ms at any time during study treatment |  | Measured through Week 65 | 
| Occurrence of QTcF change from baseline of ≥30 ms and ≤60 ms, and ≥60 ms at any time during study treatment |  | Measured through Week 65 | 
| Time to stable culture conversion in solid media | 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 | Measured through Week 65 | 
| Proportion of participants with culture conversion across all study arms |  | Measured at Weeks 8 and 12 | 
| Proportion of participants with one or more serious adverse events (SAEs) |  | Measured through Week 65 | 
| Time (days) to positivity in liquid culture (MGIT) after start of treatment across study arms |  | Measured through Week 65 | 
| Change in chest X-ray score from baseline to end of treatment in each Arm (week 13 in Arm 1, week 26 in Arm 2) | The chest X-ray will be posterior-anterior. Extent of disease (limited to one lobe or region, unilateral, bilateral, or diffuse) and cavitation status (cavities present [location] or absent) will be documented by validated numerical score for grading chest X-ray in adult smear-positive pulmonary TB (Thorax 2010; 65(10):863-9). | Measured through Week 65 | 
| Proportion of participants who have a TB relapse, from end of treatment until Week 65 |  | Measured through Week 65 | 
| Proportion of participants who have a TB recurrence, from end of treatment until Week 65 |  | Measured through 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. | 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. | 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. | 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. | Measured at Weeks 2 and 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rifapentine, clofazimine, drug-susceptible tuberculosis, tuberculosis treatment shortening