Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) Treatment Trial

Study Overview
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Brief Summary
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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.

Official Title
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Randomized Controlled Trial for Corticosteroids Versus NSAIDs With or Without Adjunctive Atorvastatin for the Treatment for Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome

Conditions
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Immune Reconstitution Inflammatory Syndrome, Immune Reconstitution Syndrome, Tuberculosis, HIV-infection/Aids

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Atorvastatin
* Drug: Naproxen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Steroid+Statin<br>Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration) | Drug: Dexamethasone<br>* Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week<br>* Other names: decadron;Drug: Atorvastatin<br>* Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)<br>* Other names: Lipitor;|
| Active Comparator: NSAID+Statin<br>Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration) | Drug: Atorvastatin<br>* Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)<br>* Other names: Lipitor;Drug: Naproxen<br>* Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week<br>* Other names: Xenobid;|
| Active Comparator: Steroid+Placebo<br>Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Placebo | Drug: Dexamethasone<br>* Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week<br>* Other names: decadron;Drug: Placebo<br>* Atorvastatin placebo<br>|
| Active Comparator: NSAID+Placebo<br>Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Placebo | Drug: Naproxen<br>* Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week<br>* Other names: Xenobid;Drug: Placebo<br>* Atorvastatin placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days of hospitalization combined with outpatient therapeutic procedures |  | 56 days | 
| Study medicine discontinuation | (e.g. switching to open-label medication) | 28 days | 
| Karnofsky Performance Status Scale at day 7 and 28; |  | Day 7 and Day 28 | 
| Incidence of Adverse Events | DAIDS Grading Scale 3-5 events | 56 days | 
| Radiologic improvement at 2 weeks; |  | 14 days | 
| Mortality |  | 56 days | 
| CD4 count change |  | 28 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TB, AIDS, HIV, IRIS, immune reconstitution inflammatory syndrome, anti-inflammatory, treatment