Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) Treatment Trial
- Conditions
- Immune Reconstitution Inflammatory SyndromeImmune Reconstitution SyndromeTuberculosisHIV-infection/Aids
- Interventions
- Registration Number
- NCT01442428
- Lead Sponsor
- University of Minnesota
- Brief Summary
Tuberculosis is the most common opportunistic infection (OI) in HIV-infected persons worldwide, including in South East Asia. Significant numbers of patients experience tuberculosis-related paradoxical immune reconstitution inflammatory syndrome (TB-IRIS) after ART initiation, yet the optimal treatment of TB-IRIS is unknown. A recent randomized-controlled trial showed the benefit of prednisone over placebo in reduction of days of hospitalization and invasive procedures. The investigators hypothesize that nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as corticosteroids for treatment of non-life threatening TB-IRIS in HIV-infected patients and hypothesize that adjunctive treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (Statins) may improve the outcomes. This is a randomized controlled trial with a 2x2 factorial design to test the relative benefit of corticosteroids, NSAIDS, and Statins for the symptomatic and immunologic control of TB-IRIS.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
- HIV-1 infection documented by any locally licensed ELISA or rapid HIV test kit.
- Age >18 years
- Paradoxical TB-IRIS diagnosed by case definition (see section 5.2)
- Ability and willingness of the participant or legal guardian/representative to give informed consent. Receiving appropriate ART and anti-TB therapy, as judged by the site investigator
- Inability to take oral medication;
- Receiving chemotherapy, immunosuppressant, corticosteroid, NSAID, or statin medications; (ASA is acceptable)
- Cannot or unlikely to attend regular clinic visits;
- Known allergy to NSAIDs, statins or corticosteroids;
- Liver transaminase > 2 times the upper limit of normal within 60 days of enrollment;
- History of myositis/myopathy;
- High Investigator Suspicion of anti-TB treatment failure due to TB-resistance or medication non-adherence;
- Receiving ongoing azole anti-fungal for treatment or secondary prophylaxis of cryptococcosis, histoplasmosis or penicilliosis;
- Serious co-morbidities, co-infections, or laboratory values who should not receive NSAIDs, steroid or statins, as judged by the site investigator;
- Minimal IRIS reaction which is unlikely to require treatment, as judged by the site investigator;
- Pregnancy (a negative urine pregnancy test at screening is required for women of childbearing potential) or breast feeding;
- Receiving a HIV treatment regimen containing a protease inhibitor at study entry.
Exclusion for Randomization A Only
- Life threatening TB-IRIS, as defined by:
- Acute respiratory failure; PaO2 < 60 on room air or;
- Altered mental status or;
- New focal neurological deficit or;
- Compression of the vital organs.
- Persons with uncontrolled diabetes mellitus;
- Impair kidney function, glomerular filtration rate <60 ml/min; within 72 hours of consent
- Uncontrolled congestive heart failure
- History of bleeding disorder;
- Platelet count <100,000/µL;
- History of significant gastrointestinal bleeding or ulceration;
- Prior adjunctive corticosteroid therapy for this TB episode for > 48 hr;
- Pregnancy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Steroid+Statin Dexamethasone 1. Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration) Steroid+Placebo Dexamethasone 1. Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Placebo Steroid+Placebo Placebo 1. Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Placebo NSAID+Placebo Naproxen 1. Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Placebo NSAID+Placebo Placebo 1. Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Placebo Steroid+Statin Atorvastatin 1. Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration) NSAID+Statin Atorvastatin 1. Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration) NSAID+Statin Naproxen 1. Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration)
- Primary Outcome Measures
Name Time Method Change in Clinical Symptom Score at Day 7, as measured by the 10-point visual analog scale to quantify symptom severity. Day 7 Change in serum C-reactive protein at Day 7 Day 7
- Secondary Outcome Measures
Name Time Method CD4 count change 28 days Days of hospitalization combined with outpatient therapeutic procedures 56 days Study medicine discontinuation 28 days (e.g. switching to open-label medication)
Radiologic improvement at 2 weeks; 14 days Karnofsky Performance Status Scale at day 7 and 28; Day 7 and Day 28 Incidence of Adverse Events 56 days DAIDS Grading Scale 3-5 events
Mortality 56 days Recurrence of IRIS manifestations within the 8 week study period 56 days ART or TB therapy discontinuation 56 days Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28 Day 28
Trial Locations
- Locations (3)
Ramathibodi Hospital
🇹🇭Bangkok, Thailand
Bamrasnaradura Infectious Diseases Institute
🇹🇭Nonthaburi, Thailand
Chiang Mai University
🇹🇭Chiang Mai, Thailand