Tuberculosis Clinical Trials Consortium Study 35

NCT03730181 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 6993
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

Hypotheses: Rifapentine (given as water-dispersible monolayer and/or fixed dose combination with isoniazid) dosing in HIV-infected and uninfected children ≤ 12 years of age with latent TB infection (LTBI) or with exposure to Mycobacterium tuberculosis (M. tuberculosis) will require higher mg/kg rifapentine dosing than adults to achieve adult- exposures which are correlated with efficacy in trials of TB prevention. Investigators further hypothesize that rifapentine will be safe and well-tolerated in HIV-infected and uninfected children who require treatment for LTBI.

Conditions

Latent Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Rifapentine exposure among participants by median area under the curve (AUC)

  Target AUC is no more than 25% lower than, and no more than 75% higher than, the target AUC of 522 mcg\*h/L. Data to be used for dose adjustments throughout the study and to create dosing algorithm for pediatric subgroups.

  12 weeks

Secondary Outcomes (21)

• Number of participants with Grade 3 or 4 adverse events

  24 weeks

• Proportion of participants with Grade 3 or 4 adverse events

  24 weeks

• Number of participants who discontinue study drug due to an adverse event

  12 weeks

• Proportion of participants who discontinue study drug due to an adverse event

  12 weeks

• Estimation of rifapentine absorption rate constant (ka) from plasma drug levels

  12 weeks

Study Arms (1)

Single Arm Rifapentine and Isoniazid

EXPERIMENTAL

Single arm, open label and exposure-controlled. Intervention is rifapentine given in a new fixed dose combination once-weekly, in combination with isoniazid for 12 weeks, in HIV-infected and HIV-uninfected children aged 0-12 years in whom LTBI treatment is indicated. The protocol allows for parallel enrolment of children into cohorts 1 and 2, simultaneously, using a predetermined modeled initial dose for each cohort, separately. Similarly, cohorts 3 and 4 will be enrolled in parallel, using modeled doses for each cohort, based on data from cohorts 1 and 2 and historical data from TBTC trials.

Drug: Rifapentine; Drug: Isoniazid

Interventions

Rifapentine DRUG

Rifapentine. Initial dose will be 25mg/kg. Based on interim analysis, this may be adjusted throughout the study to achieve target exposures. The standalone water-dispersible rifapentine tablet may be used to adjust the rifapentine doses, if needed.

Single Arm Rifapentine and Isoniazid

Isoniazid DRUG

Isoniazid. 25mg/kg

Single Arm Rifapentine and Isoniazid

Eligibility Criteria

• Age: 0 Years - 12 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Aged 0 - 12 years
• Documented close (household or other close exposure) for at least an average 4 hours a day over the past 6 months to a bacteriologically confirmed adult (18 years or older) source case with pulmonary TB. The adult TB source case should have confirmed drug sensitive (sputum culture confirmed or XPERT MTB/Rif \[Cepheid\] positive TB and without any evidence of drug resistance, i.e., at least XPERT MTB/Rif rifampicin susceptible or an alternative molecular or phenotypic test indicating rifampicin susceptible M. tb) OR:
• Evidence of M. tb infection (positive TST ≥ 10 mm in HIV-uninfected and TST ≥ 5 mm in HIV-infected participants or a positive commercial interferon-gamma release assay, as defined by the manufacturer)
• Confirmed HIV status:
• HIV status will be confirmed by DNA PCR and Plasma HIV-RNA if the participant is \<18 months of age.
• In participants ≥18 month of age HIV-ELISA testing will be completed. If any HIV test is positive in a child participant, regardless of age, the test result needs to be confirmed with a second HIV test, using HIV DNA or RNA PCR, from an independent sample.
• HIV-infected participants should be on an ART regimen for at least 12 weeks prior to enrolment and should be clinically stable before entering the study, regardless of CD 4 count and HIV viral load. While on study, participants must be on an efavirenz- or raltegravir-based ART regimen which should have been given for at least 14 days prior to enrolment.
• Caregiver (parent or legal guardian) gives written informed consent and assent from the child where applicable
• Weight \> 2.5 kg but \< 40 kg

You may not qualify if:

• Active TB disease (evidenced by: symptoms suggestive of TB, or suggestive findings on clinical examination, or suggestive chest radiographic findings, or positive mycobacterial culture/molecular TB tests -if culture/molecular testing was clinically indicated and was completed-, or currently on TB treatment for active disease).
• Any documented drug resistant TB (DR TB) in an identified adult source case, defined as rifampicin resistance on Xpert or any other relevant approved molecular test, or phenotypic evidence of rifampicin resistance.
• Receipt of a once-daily isoniazid regimen for \> 30 days which was given for at least 14 consecutive days in the 30 days prior to enrolment.
• Hb \< 10 mg/dl
• Weight for age z score below 2 or severe clinical malnutrition
• Known allergy or hypersensitivity to isoniazid or rifapentine
• Documented hepatic disorder including \> 5 fold elevated upper limit of normal (ULN) ALT and/or bilirubin
• Lansky play score \< 50
• Documentation of Hepatitis A or B infection
• Female adolescents who have reached menarche will not be eligible.

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• University of Stellenbosch: collaborator
• Johns Hopkins University: collaborator
• Sanofi: collaborator
• University of Cape Town: collaborator
• Chris Hani Baragwanath Academic Hospital: collaborator
• Washington D.C. Veterans Affairs Medical Center: collaborator

Study Sites (1)

Desmond Tutu TB Center, University of Stellenbosch

Stellenbosch, South Africa

Location

Related Publications (1)

• Madzime RJ, van der Laan L, du Toit S, Barnabas S, Courtney I, Brown NE, Savic R, Solans BP, Dixon MG, Tsirizani L, Denti P, Boyd R, Hesseling AC; TBTC Study 35 team. Dolutegravir concentrations in children receiving 3-month weekly isoniazid and rifapentine (3HP) for tuberculosis prevention. Microbiol Spectr. 2026 Jan 8:e0330325. doi: 10.1128/spectrum.03303-25. Online ahead of print.

  PMID: 41504451 DERIVED

MeSH Terms

Conditions

Latent Tuberculosis

Interventions

rifapentine; Isoniazid

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Anneke Hesseling, MD

  University of Stellenbosch

  PRINCIPAL INVESTIGATOR

• Mark Cotton, MD

  University of Stellenbosch

  PRINCIPAL INVESTIGATOR

• Avy Violari, MD

  PHRU

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 12, 2018
• First Posted: November 5, 2018
• Study Start: October 12, 2019
• Primary Completion: December 15, 2024
• Study Completion: May 15, 2025
• Last Updated: June 3, 2025

Record last verified: 2025-05

Locations

ZA (1)