Clinical trial NCT01442428: Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) Treatment Trial
Official title: Randomized Controlled Trial for Corticosteroids Versus NSAIDs With or Without Adjunctive Atorvastatin for the Treatment for Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
PHASE3
Conditions: Immune Reconstitution Inflammatory Syndrome
Immune Reconstitution Syndrome
Tuberculosis
HIV-infection/Aids
Keywords: TB
AIDS
HIV
IRIS
immune reconstitution inflammatory syndrome
anti-inflammatory
treatment
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: Pfizer
name: Minnesota Medical Foundation
First posted: 2011-09-28
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Change in Clinical Symptom Score at Day 7, as measured by the 10-point visual analog scale to quantify symptom severity.
timeFrame: Day 7
measure: Change in serum C-reactive protein at Day 7
timeFrame: Day 7
Secondary outcomes:
measure: Days of hospitalization combined with outpatient therapeutic procedures
timeFrame: 56 days
measure: Study medicine discontinuation
timeFrame: 28 days
measure: Karnofsky Performance Status Scale at day 7 and 28;
timeFrame: Day 7 and Day 28
measure: Incidence of Adverse Events
timeFrame: 56 days
measure: Radiologic improvement at 2 weeks;
timeFrame: 14 days
measure: Mortality
timeFrame: 56 days
measure: CD4 count change
timeFrame: 28 days
measure: Recurrence of IRIS manifestations within the 8 week study period
timeFrame: 56 days
measure: ART or TB therapy discontinuation
timeFrame: 56 days
measure: Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28
timeFrame: Day 28
Other outcomes:
Locations:
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital
city: Chiang Mai
country: Thailand
facility: Chiang Mai University
city: Nonthaburi
country: Thailand
facility: Bamrasnaradura Infectious Diseases Institute
Study officials:
affiliation: Mahidol University
name: Sasisopin Kiertiburanakul, MD, MHS
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: David R Boulware, MD, MPH
role: STUDY_CHAIR
affiliation: Memorial Sloan Kettering Cancer Center
name: Ubonvan Jongwutiwes, MD
role: STUDY_DIRECTOR
References: