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

This study has been withdrawn prior to enrollment.
(2011 Thailand flooding led to loss of GMP pharmacy, project delays, and further regulatory challenges.)
Sponsor:
Collaborators:
Pfizer
Minnesota Medical Foundation
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01442428
First received: August 30, 2011
Last updated: November 20, 2013
Last verified: November 2013

August 30, 2011
November 20, 2013
January 2014
March 2016   (final data collection date for primary outcome measure)
  • Change in Clinical Symptom Score at Day 7, as measured by the 10-point visual analog scale to quantify symptom severity. [ Time Frame: Day 7 ] [ Designated as safety issue: No ]
  • Change in serum C-reactive protein at Day 7 [ Time Frame: Day 7 ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01442428 on ClinicalTrials.gov Archive Site
  • Days of hospitalization combined with outpatient therapeutic procedures [ Time Frame: 56 days ] [ Designated as safety issue: No ]
  • Study medicine discontinuation [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    (e.g. switching to open-label medication)
  • Karnofsky Performance Status Scale at day 7 and 28; [ Time Frame: Day 7 and Day 28 ] [ Designated as safety issue: No ]
  • Incidence of Adverse Events [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
    DAIDS Grading Scale 3-5 events
  • Radiologic improvement at 2 weeks; [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • Mortality [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
  • CD4 count change [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Recurrence of IRIS manifestations within the 8 week study period [ Time Frame: 56 days ] [ Designated as safety issue: No ]
  • ART or TB therapy discontinuation [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
  • Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28 [ Time Frame: Day 28 ] [ Designated as safety issue: Yes ]
Same as current
Not Provided
Not Provided
 
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.

Not Provided
Interventional
Phase 2
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Immune Reconstitution Inflammatory Syndrome
  • Immune Reconstitution Syndrome
  • Tuberculosis
  • HIV-infection/Aids
  • Drug: Dexamethasone
    Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
    Other Name: decadron
  • Drug: Atorvastatin
    Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)
    Other Name: 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:
    • naproxen sodium
    • Aleve
    • Anaprox
    • Antalgin
    • Feminax Ultra
    • Flanax
    • Inza
    • Midol Extended Relief
    • Nalgesin
    • Naposin
    • Naprelan
    • Naprogesic
    • Naprosyn
    • Narocin
    • Proxen
    • Synflex
    • Xenobid
  • Drug: Placebo
    Atorvastatin placebo
  • Experimental: Steroid+Statin
    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)
    Interventions:
    • Drug: Dexamethasone
    • Drug: Atorvastatin
  • Active Comparator: NSAID+Statin
    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)
    Interventions:
    • Drug: Atorvastatin
    • Drug: Naproxen
  • Active Comparator: Steroid+Placebo
    1. Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week;
    2. Placebo
    Interventions:
    • Drug: Dexamethasone
    • Drug: Placebo
  • Active Comparator: NSAID+Placebo
    1. Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week;
    2. Placebo
    Interventions:
    • Drug: Naproxen
    • Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Withdrawn
0
June 2016
March 2016   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Thailand
 
NCT01442428
WS967180
Yes
University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
  • Pfizer
  • Minnesota Medical Foundation
Principal Investigator: Sasisopin Kiertiburanakul, MD, MHS Mahidol University
Study Chair: David R Boulware, MD, MPH University of Minnesota - Clinical and Translational Science Institute
Study Director: Ubonvan Jongwutiwes, MD Memorial Sloan-Kettering Cancer Center
University of Minnesota - Clinical and Translational Science Institute
November 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP