The Correlate of Risk Targeted Intervention Study

Summary

Effective tuberculosis (TB) control requires that people who progress from latent Mycobacterium tuberculosis (MTB) infection (LTBI) to TB disease are identified and treated before they infect others. A prognostic correlate of risk (COR), based on messenger ribonucleic acid (mRNA) expression signatures, which prospectively discriminates between TB cases and healthy controls, has been constructed and validated. Based on published microarray case-control datasets, the COR has 87% diagnostic sensitivity and 97% specificity for prevalent TB disease; and in two nested case-control studies, 70% prognostic sensitivity and 84% specificity for incident TB disease occurring within one year of sampling (HIV uninfected persons). Diagnostic and prognostic performance of the COR has not yet been tested in a prospective cohort.

COR+ status is not directly associated with LTBI; and may, or may not, be amenable to preventive therapy. Although effective in the short-term, preventive therapy is not recommended for treatment of LTBI in HIV uninfected adults living in high TB burden countries, due to rapid loss of protection; and treatment burden. A 3-month, 12-dose, once-weekly preventive therapy regimen of high dose Isoniazid (INH) and Rifapentine (3HP) has been recommended as equivalent to 6 months of daily INH for treatment of LTBI in low TB burden countries by the World Health Organization (WHO).

A 'screen \& treat' strategy, based on serial mass campaigns to provide targeted, short-course preventive therapy only to COR+ persons at highest risk of TB disease, may offer the solution for durable, community-wide protection in high TB burden countries. The efficacy of 3HP for prevention of incident TB disease in COR+ persons has not yet been tested in a clinical trial.

Primary Aims

1. Test whether preventive therapy (3HP) reduces the rate of incident TB disease, compared to standard of care (active surveillance), in COR+ persons.
2. Test whether COR status differentiates persons with cumulative prevalent or incident TB disease from persons without TB disease.

Secondary Aims

1. Estimate whether COR status differentiates persons at high risk for incident TB disease from persons at low risk for incident TB disease
2. Compare prognostic performance of the COR for incident TB disease with Interferon-gamma release assay (IGRA).

Conditions

• Tuberculosis

Interventions

DRUG

Isoniazid

Participants in the Treatment Arm will receive high dose Isoniazid - 15mg per kg body weight, rounded up to the nearest 100 mg; maximum dose 900 mg with Pyridoxine supplementation (25mg).

DRUG

Rifapentine

Rifapentine based on body weight (\>32kg - 50kg: 750 mg; \>50kg: 900 mg), given weekly as 12 directly observed treatment (DOT) oral doses, ideally with food, over 3 months.

Sponsors & Collaborators

• South African Tuberculosis Vaccine Initiative

  collaborator OTHER

• Aurum Institute

  collaborator OTHER

• Centre for the AIDS Programme of Research in South Africa

  collaborator NETWORK

• University of Stellenbosch

  collaborator OTHER

• London School of Hygiene and Tropical Medicine

  collaborator OTHER

• Fred Hutchinson Cancer Center

  collaborator OTHER

• University of Cape Town

  lead OTHER

Principal Investigators

• Mark Hatherill, MD, FCP (SA) · South African Tuberculosis Vaccine Initiative

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

60 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2016-09-20

Primary Completion

2019-12-31

Completion

2019-12-31

Countries

• South Africa

Study Locations