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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Tuberculosis; Immune Reconstitution Inflammatory Syndrome; HIV-infection/Aids; Immune Reconstitution Syndrome
• Intervention / Treatment: Drug: Dexamethasone; Drug: Atorvastatin; Drug: Naproxen; Drug: Placebo

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand
    • Ramathibodi Hospital
  • Chiang Mai, Thailand
    • Chiang Mai University
  • Nonthaburi, Thailand
    • Bamrasnaradura Infectious Diseases Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Steroid+Statin; 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; Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Other Names: decadron; Drug: Atorvastatin; Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population); Other Names: Lipitor
Active Comparator: NSAID+Statin; 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; Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population); Other Names: Lipitor; Drug: Naproxen; Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Other Names: Aleve; Naprosyn; Anaprox; Antalgin; Feminax Ultra; Flanax; Inza; Midol Extended Relief; Nalgesin; Naposin; Naprelan; Naprogesic; Narocin; Proxen; Synflex; Xenobid; naproxen sodium
Active Comparator: Steroid+Placebo; Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week;; Placebo	Drug: Dexamethasone; Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Other Names: decadron; Drug: Placebo; Atorvastatin placebo
Active Comparator: NSAID+Placebo; Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week;; Placebo	Drug: Naproxen; Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Other Names: Aleve; Naprosyn; Anaprox; Antalgin; Feminax Ultra; Flanax; Inza; Midol Extended Relief; Nalgesin; Naposin; Naprelan; Naprogesic; Narocin; Proxen; Synflex; Xenobid; naproxen sodium; Drug: Placebo; Atorvastatin placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: Pfizer; Minnesota Medical Foundation
• Investigators: Principal Investigator: Sasisopin Kiertiburanakul, MD, MHS, Mahidol University; Study Chair: David R Boulware, MD, MPH, University of Minnesota; Study Director: Ubonvan Jongwutiwes, MD, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Anticipated): March 1, 2016
• Study Completion (Anticipated): June 1, 2016

Study Registration Dates

• First Submitted: August 30, 2011
• First Submitted That Met QC Criteria: September 27, 2011
• First Posted (Estimate): September 28, 2011

Study Record Updates

• Last Update Posted (Estimate): November 25, 2013
• Last Update Submitted That Met QC Criteria: November 20, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: treatment; HIV; anti-inflammatory; AIDS; TB; IRIS; immune reconstitution inflammatory syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Slow Virus Diseases; HIV Infections; Syndrome; Tuberculosis; Acquired Immunodeficiency Syndrome; Immune Reconstitution Inflammatory Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antimetabolites; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Gout Suppressants; Dexamethasone; Atorvastatin; Naproxen
• Other Study ID Numbers: WS967180