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

NCT04311502 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: ACTG A536230148
• Study Type: interventional
• Target: 104
• Locations: 5 countries
• Sites: 6

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).

Conditions

HIV; Tuberculosis

Keywords

rifapentine; clofazimine; drug-susceptible tuberculosis; tuberculosis treatment shortening

Outcome Measures

Primary Outcomes (2)

• 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.

  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

  From entry through Week 65

Secondary Outcomes (26)

• Proportion of Participants With Favorable Clinical/Bacteriologic Outcome (Definition A) at 65 Weeks Post-randomization

  From entry through Week 65

• Proportion of Participants With Favorable Composite Outcome (Definition B) at 65 Weeks Post-randomization

  From entry through Week 65

• Number of Participants Who Prematurely Discontinue Their Treatment Regimen Through 65 Weeks

  From entry through Week 65

• Mean QTcF

  Measured at Weeks 2, 8, and 13 (end of investigational treatment)

• QTcF Interval Mean Change From Baseline

  Measured at baseline and Weeks 2, 8, and 13 (end of investigational treatment)

Study Arms (3)

Arm 1: Experimental

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.

Drug: Rifapentine; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Clofazimine loading dose

Arm 2: Standard of care

ACTIVE COMPARATOR

Participants received rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 weeks; then rifampicin/isoniazid (RH) for 18 weeks.

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol

Arm C: PK only subgroup

EXPERIMENTAL

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).

Drug: Rifapentine; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Clofazimine 100 MG

Interventions

Rifapentine DRUG

1200 mg once daily

Arm 1: Experimental; Arm C: PK only subgroup

Rifampicin DRUG

600 mg once daily

Arm 2: Standard of care

Isoniazid DRUG

300 mg once daily

Arm 1: Experimental; Arm 2: Standard of care; Arm C: PK only subgroup

Pyrazinamide DRUG

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

Arm 1: Experimental; Arm 2: Standard of care; Arm C: PK only subgroup

Ethambutol DRUG

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

Arm 1: Experimental; Arm 2: Standard of care; Arm C: PK only subgroup

Clofazimine loading dose DRUG

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

Arm 1: Experimental

Clofazimine 100 MG DRUG

100 mg once daily

Arm C: PK only subgroup

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (6)

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

Port-au-Prince, HT-6110, Haiti

Location

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, 411001, India

Location

Malawi CRS

Lilongwe, Central Region, Malawi

Location

Blantyre CRS

Blantyre, 1131, Malawi

Location

CAPRISA eThekwini CRS

Durban, KwaZulu-Natal, 4013, South Africa

Location

Milton Park CRS

Harare, Zimbabwe

Location

Related Publications (2)

• Mugodhi F, Kanyama C, Makiya F, Metcalfe J, Potani C, Scarsi KK, Weir I, Furin J. "Six months is a lot of time to lie": Anticipated stigma, disclosure and treatment preferences among participants in a tuberculosis therapeutic trial. Res Sq [Preprint]. 2025 Dec 22:rs.3.rs-8277920. doi: 10.21203/rs.3.rs-8277920/v1.

  PMID: 41510291 DERIVED

• Metcalfe JZ, Weir IR, Scarsi KK, Mendoza-Ticona A, Pierre S, Hall L, Leon-Cruz J, Svensson EM, Koele SE, Samaneka W, Kanyama C, Yohane M, Nevrekar N, Ntsalaze B, Marc JB, Goth M, Maartens G, Chaisson R; ACTG A5362 study team. A 3-month clofazimine-rifapentine-containing regimen for drug-susceptible tuberculosis versus standard of care (Clo-Fast): a randomised, open-label, phase 2c clinical trial. Lancet Infect Dis. 2026 Jan;26(1):46-54. doi: 10.1016/S1473-3099(25)00436-0. Epub 2025 Sep 4.

  PMID: 40915311 DERIVED

Related Links

• DAIDS AE Grading Table
• Manual for Expedited Reporting of Adverse Events to DAIDS
• A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary tuberculosis

MeSH Terms

Conditions

Tuberculosis

Interventions

rifapentine; Rifampin; Isoniazid; Pyrazinamide; Ethambutol; Clofazimine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines; Phenazines; Heterocyclic Compounds, 3-Ring

Limitations and Caveats

Enrollment to this study was terminated early based on a recommendation from the independent DSMB for the study. This was due to the high rate of unfavorable outcomes and recurrences in Arm 1. As a consequence, the study had reduced precision to evaluate the primary biomarker outcome related to time to stable culture conversion.

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• John Metcalfe, MD, PhD, MPH

  University of California, San Francisco

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2020
• First Posted: March 17, 2020
• Study Start: November 5, 2021
• Primary Completion: June 24, 2024
• Study Completion: June 24, 2025
• Last Updated: August 27, 2025
• Results First Posted: August 27, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) Network by NIH.
• Access Criteria: * With whom? * Researchers who provide a methodologically sound proposal for use of the data that is approved by the ACTG. * For what types of analyses? * To achieve aims in the proposal approved by the ACTG Group. * By what mechanism will data be made available? * Researchers may submit a request for access to data using the ACTG "Data Request" form at: https://submit.mis.s-3.net/ Researchers of approved proposals will need to sign an ACTG Data Use Agreement before receiving the data.

Locations

IN (1); ZA (1); HA (1); MA (2); ZI (1)