Clinical trial NCT02735590: The Correlate of Risk Targeted Intervention Study
Official title: A Randomized, Partially-blinded, Clinical Trial of Isoniazid and Rifapentine (3HP) Therapy to Prevent Pulmonary Tuberculosis in High-risk Individuals Identified by a Transcriptomic Correlate of Risk
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Tuberculosis
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: South African Tuberculosis Vaccine Initiative
name: Aurum Institute
name: Centre for the AIDS Programme of Research in South Africa
name: University of Stellenbosch
name: London School of Hygiene and Tropical Medicine
name: Fred Hutchinson Cancer Center
First posted: 2016-04-12
Enrollment: 2927
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief 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).


Eligibility criteria: Inclusion Criteria:

1. Written informed consent
2. Aged ≥18 and \<60 years
3. Known COR status (- or +)
4. Known HIV status
5. Women of child-bearing potential who are not surgically sterilized must agree to practice adequate contraception (barrier method or non-hormonal intrauterine device, alone or in addition to systemic hormonal contraceptive method) or abstain from heterosexual intercourse during the first 3 months on study.
6. Likely to remain in follow-up and adhere to protocol requirements

Exclusion Criteria:

1. HIV infection
2. Pregnant or lactating
3. Diagnosed with TB disease within last 3 years
4. Household exposure to a TB patient with known multi-drug resistant (MDR-) TB disease within last 3 years
5. Body weight \<40kg
6. Known allergy to INH or Rifamycins
7. Receiving antiarrhythmic, antidepressant, antipsychotic, antihypertensive, anticonvulsant, anticoagulant, or (inhaled or oral) corticosteroid therapy
8. Any medical, surgical, or other condition, including but not limited to known diabetes mellitus (requiring oral or injectable therapy), liver disease, porphyria, peripheral neuropathy, epilepsy, psychosis, or alcoholism, that in the opinion of the Investigator is likely to interfere with COR performance; safety and efficacy of the investigational products (IP); or adherence to protocol requirements

Primary outcomes:
measure: Treatment Efficacy
timeFrame: 15 months
measure: Performance of COR
timeFrame: 15 months
Secondary outcomes:
Other outcomes:
Locations:
city: Durban
country: South Africa
facility: Centre for the Aids Programme of Research in South Africa (CAPRISA)
state: KwaZulu-Natal
city: Klerksdorp
country: South Africa
facility: Aurum Institute
state: North West Province
city: Rustenburg
country: South Africa
facility: Aurum Institute
state: North West
city: Cape Town
country: South Africa
facility: Stellenbosch Immunology Research Group
state: Western Cape
city: Worcester
country: South Africa
facility: South African Tuberculosis Vaccine Initiative (SATVI)
state: Western Cape
Study officials:
affiliation: South African Tuberculosis Vaccine Initiative
name: Mark Hatherill, MD, FCP (SA)
role: PRINCIPAL_INVESTIGATOR
References:
citation: Scriba TJ, Fiore-Gartland A, Penn-Nicholson A, Mulenga H, Kimbung Mbandi S, Borate B, Mendelsohn SC, Hadley K, Hikuam C, Kaskar M, Musvosvi M, Bilek N, Self S, Sumner T, White RG, Erasmus M, Jaxa L, Raphela R, Innes C, Brumskine W, Hiemstra A, Malherbe ST, Hassan-Moosa R, Tameris M, Walzl G, Naidoo K, Churchyard G, Hatherill M; CORTIS-01 Study Team. Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial. Lancet Infect Dis. 2021 Mar;21(3):354-365. doi: 10.1016/S1473-3099(20)30914-2. Epub 2021 Jan 25.