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

  • STATUS
    Recruiting
  • End date
    Nov 18, 2022
  • participants needed
    185
  • sponsor
    National Institute of Allergy and Infectious Diseases (NIAID)
Updated on 26 July 2021
hysterectomy
antiretroviral therapy
tuberculosis
hiv test
isoniazid
HIV Vaccine
antibody test
hiv-1 rna measurement

Summary

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).

Description

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).

Details
Condition Tuberculosis, HIV, HIV positive, HIV infection, AIDS Vaccines, HIV Infections, tb (tuberculosis), human immunodeficiency virus, hiv disease, HIV Vaccine, hiv vaccines
Treatment Isoniazid (INH), Rifapentine (RPT), Pyridoxine (vitamin B6), Clofazimine (CFZ), Pyrazinamide (PZA), Ethambutol (EMB), Rifampicin (RIF)
Clinical Study IdentifierNCT04311502
SponsorNational Institute of Allergy and Infectious Diseases (NIAID)
Last Modified on26 July 2021

Eligibility

Yes No Not Sure

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
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