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

This study is not yet open for participant recruitment.
Verified February 2013 by University of Minnesota - Clinical and Translational Science Institute
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: February 27, 2013
Last verified: February 2013
History of Changes
  Purpose

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 Intervention 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 Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 100
Study Start Date: July 2013
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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, GFR <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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01442428

Contacts
Contact: Sasisopin Kiertiburanakul, MD, MHS +662.201.1581 rasal@mahidol.ac.th
Contact: Ubonvan Jongwutiwes, MD +1.651.528.2056 ubonvan@gmail.com

Locations
Thailand
Ramathibodi Hospital
Bangkok, Thailand
Chiang Mai University
Chiang Mai, Thailand
Bamrasnaradura Infectious Diseases Institute
Nonthaburi, Thailand
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Pfizer
Minnesota Medical Foundation
Investigators
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
  More Information

No publications provided

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01442428     History of Changes
Other Study ID Numbers: WS967180
Study First Received: August 30, 2011
Last Updated: February 27, 2013
Health Authority: Thailand: Ethical Committee
United States: Institutional Review Board

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
TB
AIDS
HIV
IRIS
 immune reconstitution inflammatory syndrome
anti-inflammatory
treatment

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Tuberculosis
Immune Reconstitution Inflammatory Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Mycobacterium Infections
Actinomycetales Infections
 Gram-Positive Bacterial Infections
Bacterial Infections
Naproxen
Anti-Inflammatory Agents, Non-Steroidal
Dexamethasone acetate
Dexamethasone
BB 1101
Atorvastatin
Dexamethasone 21-phosphate
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on March 03, 2013