Using Biomarkers to Predict TB Treatment Duration

NCT02821832 | Completed Phase 2 Results

• 2 other identifiers: 99991613316-I-N133
• Study Type: interventional
• Target: 946
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Tuberculosis (TB) is a bacterial lung infection. Typical treatment using anti-TB drugs lasts about 6 months. Some people with less severe TB might not need to take the drugs that long. Researchers think a PET/CT lung scan along with estimating how much TB is in the lungs might show who will be cured after only 4 months of treatment. Objective: To demonstrate that 4 months of treatment is not inferior to 6 months of treatment for people with less severe TB. Eligibility: People 18-75 years old who have TB treatable with standard TB drugs Design: Participants will be screened with: Medical history Physical exam Blood and urine tests HIV test Sputum sample: Participants will be asked to cough sputum into a cup. Chest x-ray Participants will start TB drugs. They will have visits at weeks 1, 2, 4, 8, 12, and about 6 more times during the 18-month study. Visits include: Sputum samples Physical exam Blood tests PET/CT scans at 2-3 visits: Participants fast for about 6 hours before the scan. Participants get FDG, a type of sugar that gives off a small amount of radiation, through an arm vein. They lie on a table in a machine that takes pictures of the body. Chest x-rays at 1-2 visits Participants who we believe are likely to be cured at 4 months will be randomly assigned to get either 6 months of treatment or 4 months of treatment. Participants may be asked to join a substudy using their sputum samples or additional blood tests.

Conditions

Pulmonary Tuberculosis

Keywords

Drug-Resistance; Heteroresistance; Relapse-markers; Medical Imaging; Treatment-shortening

Outcome Measures

Primary Outcomes (1)

• Comparison of the Rate of Treatment Success at 18 Months (After Treatment Initiation) Between Arms B and C

  Estimation of the lower bound of a one-sided 95% confidence interval of the difference in success rates between arms B and C. If the lower bound is greater than -7%, this will be evidence that the treatment-shortening arm is not inferior to the standard duration arm.

  18 months

Secondary Outcomes (1)

• Radiologic, Immunologic and Microbiologic Measures

  18 months

Study Arms (3)

Arm A - Expected high risk of relapse, standard of care TB treatment

OTHER

Expected high risk of relapse, standard of care TB treatment

Procedure: Saliva collection; Procedure: Urine collection; Procedure: Sputum collection; Procedure: Blood Collection; Radiation: PET/CT Scan; Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol

Arm B - Expected low risk of relapse, standard of care TB treatment

ACTIVE COMPARATOR

Expected low risk of relapse, standard of care TB treatment

Procedure: Saliva collection; Procedure: Urine collection; Procedure: Sputum collection; Procedure: Blood Collection; Radiation: PET/CT Scan; Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol

Arm C - Expected low risk of relapse, shortened TB treatment

EXPERIMENTAL

Expected low risk of relapse, shortened TB treatment

Procedure: Saliva collection; Procedure: Urine collection; Procedure: Sputum collection; Procedure: Blood Collection; Radiation: PET/CT Scan; Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol

Interventions

Saliva collection PROCEDURE

For biomarker assessments

Arm A - Expected high risk of relapse, standard of care TB treatment; Arm B - Expected low risk of relapse, standard of care TB treatment; Arm C - Expected low risk of relapse, shortened TB treatment

Urine collection PROCEDURE

For biomarker assessments

Arm A - Expected high risk of relapse, standard of care TB treatment; Arm B - Expected low risk of relapse, standard of care TB treatment; Arm C - Expected low risk of relapse, shortened TB treatment

Sputum collection PROCEDURE

For primary endpoint assessments and other biomarker assessments

Arm A - Expected high risk of relapse, standard of care TB treatment; Arm B - Expected low risk of relapse, standard of care TB treatment; Arm C - Expected low risk of relapse, shortened TB treatment

Blood Collection PROCEDURE

For biomarker and eligibility assessments

Arm A - Expected high risk of relapse, standard of care TB treatment; Arm B - Expected low risk of relapse, standard of care TB treatment; Arm C - Expected low risk of relapse, shortened TB treatment

PET/CT Scan RADIATION

Imaging of the lungs to establish disease extent and severity

Arm A - Expected high risk of relapse, standard of care TB treatment; Arm B - Expected low risk of relapse, standard of care TB treatment; Arm C - Expected low risk of relapse, shortened TB treatment

Isoniazid, Rifampicin, Pyrazinamide and Ethambutol DRUG

Treatment-standard of care

Arm A - Expected high risk of relapse, standard of care TB treatment; Arm B - Expected low risk of relapse, standard of care TB treatment; Arm C - Expected low risk of relapse, shortened TB treatment

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 75 years with body weight from 35 kg to 90 kg
• Has not been treated for active TB within the past 3 years
• Not yet on TB treatment
• Xpert positive for M.tb
• Rifampin-sensitive pulmonary tuberculosis as indicated by Xpert
• Laboratory parameters within previous 14 days before enrollment:
• Serum AST and ALT \<3x upper limit of normal (ULN)
• Creatinine \<2x ULN
• Hemoglobin \>7.0 g/dL
• Platelet count \>50 x10(9) cells/L
• Able and willing to return for follow-up visits
• Able and willing to provide informed consent to participate in the study
• Willing to undergo an HIV test
• At sites with sufficient SARS-CoV-2 testing capacity and personal protective equipment for study staff, willing to undergo COVID-19 testing:
• viral RNA PCR testing for SARS-CoV-2 to determine active infection and antibody testing for SARS-CoV-2 to determine prior infection

You may not qualify if:

• Clinical suspicion of or confirmed extrapulmonary TB, including pleural TB
• Pregnant or desiring/trying to become pregnant in the next 6 months or breastfeeding.
• HIV infected
• Currently COVID-19 infected
• Unable to take oral medications
• Diabetes as defined by point of care HbA1c greater than 6.5%, random glucose greater than 200 mg/dL (or 11.1 mmol/L), fasting plasma glucose greater than or equal to 126 mg/dL (or 7.0 mmol/L), or the presence of any antidiabetic agent (including traditional medicines) as a concomitant medicine
• Disease complications or concomitant illnesses that may compromise safety or interpretation of trial endpoints, such as known diagnosis of chronic inflammatory condition (e.g. sarcoidosis, rheumatoid arthritis, connective tissue disorder)
• Use of immunosuppressive medications, such as TNF-alpha inhibitors or systemic or inhaled corticosteroids, within the past 2 weeks
• Use of any investigational drug in the previous 3 months
• Substance or alcohol abuse that in the opinion of the investigator may interfere with the participant's adherence to study procedures.
• Any person for whom the physician feels this study is not appropriate

Sponsors & Collaborators

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

Study Sites (1)

Clinical Infectious Diseases Research Initiative (Khayelitsha site)

Cape Town, South Africa

Location

Related Publications (4)

• Jindani A, Harrison TS, Nunn AJ, Phillips PP, Churchyard GJ, Charalambous S, Hatherill M, Geldenhuys H, McIlleron HM, Zvada SP, Mungofa S, Shah NA, Zizhou S, Magweta L, Shepherd J, Nyirenda S, van Dijk JH, Clouting HE, Coleman D, Bateson AL, McHugh TD, Butcher PD, Mitchison DA; RIFAQUIN Trial Team. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1599-608. doi: 10.1056/NEJMoa1314210.

  PMID: 25337749 BACKGROUND

• Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, Pappas F, Phillips PP, Nunn AJ; REMoxTB Consortium. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1577-87. doi: 10.1056/NEJMoa1407426. Epub 2014 Sep 7.

  PMID: 25196020 BACKGROUND

• Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, Odhiambo J, Amukoye E, Bah B, Kassa F, N'Diaye A, Rustomjee R, de Jong BC, Horton J, Perronne C, Sismanidis C, Lapujade O, Olliaro PL, Lienhardt C; OFLOTUB/Gatifloxacin for Tuberculosis Project. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1588-98. doi: 10.1056/NEJMoa1315817.

  PMID: 25337748 BACKGROUND

• Chen RY, Via LE, Dodd LE, Walzl G, Malherbe ST, Loxton AG, Dawson R, Wilkinson RJ, Thienemann F, Tameris M, Hatherill M, Diacon AH, Liu X, Xing J, Jin X, Ma Z, Pan S, Zhang G, Gao Q, Jiang Q, Zhu H, Liang L, Duan H, Song T, Alland D, Tartakovsky M, Rosenthal A, Whalen C, Duvenhage M, Cai Y, Goldfeder LC, Arora K, Smith B, Winter J, Barry Iii CE; Predict TB Study Group. Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial. Gates Open Res. 2017 Nov 6;1:9. doi: 10.12688/gatesopenres.12750.1.

  PMID: 29528048 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Urine Specimen Collection; Blood Specimen Collection; Isoniazid; Rifampin; Pyrazinamide; Ethambutol

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Punctures; Surgical Procedures, Operative; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines

Limitations and Caveats

The COVID-19 pandemic forced the temporary halt of all study activities, which led to some missed visits. As study activities resumed, some study visits and PET/CT scans needed to be done out-of-window. All of the COVID-related protocol deviations can be attributed to clinical site restrictions and safety precautions taken to protect study staff and participants.

Results Point of Contact

• Title: Dr. Clif E. Barry 3rd
• Organization: National Institute of Allergy and Infectious Diseases

cbarry@niaid.nih.gov

301-693-4665

Study Officials

• Clifton E Barry, Ph.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: June 29, 2016
• First Posted: July 4, 2016
• Study Start: June 21, 2017
• Primary Completion: October 9, 2021
• Study Completion: February 28, 2022
• Last Updated: April 17, 2024
• Results First Posted: December 20, 2022

Record last verified: 2024-04

Locations

ZA (1)