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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01442428
Recruitment Status : Withdrawn (2011 Thailand flooding led to loss of GMP pharmacy, project delays, and further regulatory challenges.)
First Posted : September 28, 2011
Last Update Posted : November 25, 2013
Sponsor:
Collaborators:
Pfizer
Minnesota Medical Foundation
Information provided by (Responsible Party):
University of Minnesota

Study Description
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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.

Condition or disease Intervention/treatment Phase
Immune Reconstitution Inflammatory Syndrome Immune Reconstitution Syndrome Tuberculosis HIV-infection/Aids Drug: Dexamethasone Drug: Atorvastatin Drug: Naproxen Drug: Placebo Phase 2 Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : January 2014
Estimated Primary Completion Date : March 2016
Estimated Study Completion Date : June 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arms and Interventions
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Arm Intervention/treatment
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)
 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
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)
 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
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
 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: Placebo
Atorvastatin 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
 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


Outcome Measures
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Primary Outcome Measures :
  1. 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 ]
  2. Change in serum C-reactive protein at Day 7 [ Time Frame: Day 7 ]

Secondary Outcome Measures :
  1. Days of hospitalization combined with outpatient therapeutic procedures [ Time Frame: 56 days ]
  2. Study medicine discontinuation [ Time Frame: 28 days ]
    (e.g. switching to open-label medication)

  3. Karnofsky Performance Status Scale at day 7 and 28; [ Time Frame: Day 7 and Day 28 ]
  4. Incidence of Adverse Events [ Time Frame: 56 days ]
    DAIDS Grading Scale 3-5 events

  5. Radiologic improvement at 2 weeks; [ Time Frame: 14 days ]
  6. Mortality [ Time Frame: 56 days ]
  7. CD4 count change [ Time Frame: 28 days ]
  8. Recurrence of IRIS manifestations within the 8 week study period [ Time Frame: 56 days ]
  9. ART or TB therapy discontinuation [ Time Frame: 56 days ]
  10. Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28 [ Time Frame: Day 28 ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01442428


Locations
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Thailand
Ramathibodi Hospital
Bangkok, Thailand
Chiang Mai University
Chiang Mai, Thailand
Bamrasnaradura Infectious Diseases Institute
Nonthaburi, Thailand
Sponsors and Collaborators
University of Minnesota
Pfizer
Minnesota Medical Foundation
Investigators
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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
More Information
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Layout table for additonal information
Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT01442428    
Other Study ID Numbers: WS967180
First Posted: September 28, 2011    Key Record Dates
Last Update Posted: November 25, 2013
Last Verified: November 2013
Keywords provided by University of Minnesota:
TB
AIDS
HIV
IRIS
 immune reconstitution inflammatory syndrome
anti-inflammatory
treatment
Additional relevant MeSH terms:
Layout table for MeSH terms
HIV Infections
Tuberculosis
Acquired Immunodeficiency Syndrome
Immune Reconstitution Inflammatory Syndrome
Syndrome
Disease
Pathologic Processes
Blood-Borne Infections
Communicable Diseases
Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
 Virus Diseases
Genital Diseases
Urogenital Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Slow Virus Diseases
Dexamethasone
Naproxen
Atorvastatin
Anti-Inflammatory Agents