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

NCT01442428 | Withdrawn Phase 2 DMC

• 1 other identifier: WS967180
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 3

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.

Conditions

Immune Reconstitution Inflammatory Syndrome; Immune Reconstitution Syndrome; Tuberculosis; HIV-infection/Aids

Keywords

TB; AIDS; HIV; IRIS; immune reconstitution inflammatory syndrome; anti-inflammatory; treatment

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (10)

• Days of hospitalization combined with outpatient therapeutic procedures

  56 days

• Study medicine discontinuation

  28 days

• Karnofsky Performance Status Scale at day 7 and 28;

  Day 7 and Day 28

• Incidence of Adverse Events

  56 days

• Radiologic improvement at 2 weeks;

  14 days

Study Arms (4)

Steroid+Statin

EXPERIMENTAL

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)

Drug: Dexamethasone; Drug: Atorvastatin

NSAID+Statin

ACTIVE COMPARATOR

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)

Drug: Atorvastatin; Drug: Naproxen

Steroid+Placebo

ACTIVE COMPARATOR

1. Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Placebo

Drug: Dexamethasone; Drug: Placebo

NSAID+Placebo

ACTIVE COMPARATOR

1. Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; 2. Placebo

Drug: Naproxen; Drug: Placebo

Interventions

Dexamethasone DRUG

Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week

Also known as: decadron

Steroid+Placebo; Steroid+Statin

Atorvastatin DRUG

Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)

Also known as: Lipitor

NSAID+Statin; Steroid+Statin

Naproxen DRUG

Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week

Also known as: naproxen sodium, Aleve, Anaprox, Antalgin, Feminax Ultra, Flanax, Inza, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Proxen, Synflex, Xenobid

NSAID+Placebo; NSAID+Statin

Placebo DRUG

Atorvastatin placebo

NSAID+Placebo; Steroid+Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• Life threatening TB-IRIS, as defined by:
• Acute respiratory failure; PaO2 \< 60 on room air or;
• Altered mental status or;

Sponsors & Collaborators

• University of Minnesota: lead
• Pfizer: collaborator
• Minnesota Medical Foundation: collaborator

Study Sites (3)

Ramathibodi Hospital

Bangkok, Thailand

Location

Chiang Mai University

Chiang Mai, Thailand

Location

Bamrasnaradura Infectious Diseases Institute

Nonthaburi, Thailand

Location

MeSH Terms

Conditions

Immune Reconstitution Inflammatory Syndrome; Tuberculosis; Acquired Immunodeficiency Syndrome

Interventions

Dexamethasone; Calcium Dobesilate; Atorvastatin; Naproxen

Condition Hierarchy (Ancestors)

Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Naphthaleneacetic Acids; Naphthalenes; Polycyclic Aromatic Hydrocarbons

Study Officials

• Sasisopin Kiertiburanakul, MD, MHS

  Mahidol University

  PRINCIPAL INVESTIGATOR

• David R Boulware, MD, MPH

  University of Minnesota

  STUDY CHAIR

• Ubonvan Jongwutiwes, MD

  Memorial Sloan Kettering Cancer Center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2011
• First Posted: September 28, 2011
• Study Start: January 1, 2014
• Primary Completion: March 1, 2016
• Study Completion: June 1, 2016
• Last Updated: November 25, 2013

Record last verified: 2013-11

Locations

TH (3)