The Correlate of Risk Targeted Intervention Study

NCT02735590 | Unknown Phase 2 DMC

• 1 other identifier: CORTIS-01
• Study Type: interventional
• Target: 2,927
• Locations: 1 country
• Sites: 5

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. 1.Test whether preventive therapy (3HP) reduces the rate of incident TB disease, compared to standard of care (active surveillance), in COR+ persons.
2. 2.Test whether COR status differentiates persons with cumulative prevalent or incident TB disease from persons without TB disease.
3. 3.Estimate whether COR status differentiates persons at high risk for incident TB disease from persons at low risk for incident TB disease
4. 4.Compare prognostic performance of the COR for incident TB disease with Interferon-gamma release assay (IGRA).

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (2)

• Treatment Efficacy

  Treatment efficacy (TE) will be evaluated by comparing the incidence of endpoint-defined TB disease over 15 months in treated COR+ versus untreated COR+ participants.

  15 months

• Performance of COR

  The performance of the COR will be evaluated by comparing the cumulative incidence of endpoint-defined TB disease over 15 months in untreated COR+ versus untreated COR- participants

  15 months

Study Arms (2)

Open-label 3HP

EXPERIMENTAL

Participants in the Treatment Arm will receive high dose INH (15mg per kg body weight, rounded up to the nearest 100 mg; maximum dose 900 mg) with Pyridoxine supplementation (25mg), and 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. Dispensing of IP and Directly Observed Treatment (DOT) field visits in Treatment Arm participants will be performed by staff members not involved in TB symptom screening or investigation. Participants receiving 3HP who develop symptoms of hepatotoxicity will be evaluated by an Investigator.

Drug: Isoniazid; Drug: Rifapentine

Baseline Screening; Active Surveillance

NO INTERVENTION

Adult volunteers living in TB hyperendemic communities of South Africa will be consented and screened. Individuals with HIV infection and conditions likely to affect the performance of the COR assay, or the safety and/or efficacy of the 3HP investigational regimen, will not be enrolled. Active surveillance for TB disease (Observation Arm), including regular symptom screening and symptom-targeted TB investigation (all participants) will be conducted on this Arm.

Interventions

Isoniazid DRUG

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).

Open-label 3HP

Rifapentine DRUG

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.

Open-label 3HP

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Written informed consent
• Aged ≥18 and \<60 years
• Known COR status (- or +)
• Known HIV status
• 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.
• Likely to remain in follow-up and adhere to protocol requirements

You may not qualify if:

• HIV infection
• Pregnant or lactating
• Diagnosed with TB disease within last 3 years
• Household exposure to a TB patient with known multi-drug resistant (MDR-) TB disease within last 3 years
• Body weight \<40kg
• Known allergy to INH or Rifamycins
• Receiving antiarrhythmic, antidepressant, antipsychotic, antihypertensive, anticonvulsant, anticoagulant, or (inhaled or oral) corticosteroid therapy
• 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

Sponsors & Collaborators

• University of Cape Town: lead
• South African Tuberculosis Vaccine Initiative: collaborator
• Aurum Institute: collaborator
• Centre for the AIDS Programme of Research in South Africa: collaborator
• University of Stellenbosch: collaborator
• London School of Hygiene and Tropical Medicine: collaborator
• Fred Hutchinson Cancer Center: collaborator

Study Sites (5)

Centre for the Aids Programme of Research in South Africa (CAPRISA)

Durban, KwaZulu-Natal, 4013, South Africa

Location

Aurum Institute

Klerksdorp, North West, 2571, South Africa

Location

Aurum Institute

Rustenburg, North West, 0300, South Africa

Location

Stellenbosch Immunology Research Group

Cape Town, Western Cape, 7505, South Africa

Location

South African Tuberculosis Vaccine Initiative (SATVI)

Worcester, Western Cape, 6850, South Africa

Location

Related Publications (1)

• 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.

  PMID: 33508224 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Isoniazid; rifapentine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Study Officials

• Mark Hatherill, MD, FCP (SA)

  South African Tuberculosis Vaccine Initiative

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: National Principal Investigator

Study Record Dates

• First Submitted: April 6, 2016
• First Posted: April 12, 2016
• Study Start: September 20, 2016
• Primary Completion: December 31, 2019
• Study Completion: December 31, 2019
• Last Updated: December 24, 2018

Record last verified: 2018-12

Data Sharing

• IPD Sharing: Will share

Locations

ZA (5)