The Correlate of Risk Targeted Intervention Study (CORTIS)
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| ClinicalTrials.gov Identifier: NCT02735590 |
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Recruitment Status : Unknown
Verified December 2018 by Mark Hatherill, University of Cape Town.
Recruitment status was: Active, not recruiting
First Posted : April 12, 2016
Last Update Posted : December 24, 2018
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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
- Test whether preventive therapy (3HP) reduces the rate of incident TB disease, compared to standard of care (active surveillance), in COR+ persons.
- Test whether COR status differentiates persons with cumulative prevalent or incident TB disease from persons without TB disease.
Secondary Aims
- Estimate whether COR status differentiates persons at high risk for incident TB disease from persons at low risk for incident TB disease
- Compare prognostic performance of the COR for incident TB disease with Interferon-gamma release assay (IGRA).
| Condition or disease | Intervention/treatment | Phase |
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| Tuberculosis | Drug: Isoniazid Drug: Rifapentine | Phase 2 Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 2927 participants |
| Allocation: | Randomized |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Prevention |
| 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 |
| Actual Study Start Date : | September 20, 2016 |
| Estimated Primary Completion Date : | December 31, 2019 |
| Estimated Study Completion Date : | December 31, 2019 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Open-label 3HP
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.
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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. |
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No Intervention: Baseline Screening; Active Surveillance
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.
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- Treatment Efficacy [ Time Frame: 15 months ]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.
- Performance of COR [ Time Frame: 15 months ]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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years to 60 Years (Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02735590
| South Africa | |
| Centre for the Aids Programme of Research in South Africa (CAPRISA) | |
| Durban, KwaZulu-Natal, South Africa, 4013 | |
| Aurum Institute | |
| Klerksdorp, North West Province, South Africa, 2571 | |
| Aurum Institute | |
| Rustenburg, North West, South Africa, 0300 | |
| Stellenbosch Immunology Research Group | |
| Cape Town, Western Cape, South Africa, 7505 | |
| South African Tuberculosis Vaccine Initiative (SATVI) | |
| Worcester, Western Cape, South Africa, 6850 | |
| Principal Investigator: | Mark Hatherill, MD, FCP (SA) | South African Tuberculosis Vaccine Initiative |
| Responsible Party: | Mark Hatherill, National Principal Investigator, University of Cape Town |
| ClinicalTrials.gov Identifier: | NCT02735590 |
| Other Study ID Numbers: |
CORTIS-01 |
| First Posted: | April 12, 2016 Key Record Dates |
| Last Update Posted: | December 24, 2018 |
| Last Verified: | December 2018 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Publications |
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Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Isoniazid Rifapentine Antitubercular Agents |
Anti-Bacterial Agents Anti-Infective Agents Fatty Acid Synthesis Inhibitors Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Antibiotics, Antitubercular Leprostatic Agents |