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

Primary Purpose

Immune Reconstitution Inflammatory Syndrome, Immune Reconstitution Syndrome, Tuberculosis

Status
Withdrawn
Phase
Phase 2
Locations
Thailand
Study Type
Interventional
Intervention
Dexamethasone
Atorvastatin
Naproxen
Placebo
Sponsored by
University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Immune Reconstitution Inflammatory Syndrome focused on measuring TB, AIDS, HIV, IRIS, immune reconstitution inflammatory syndrome, anti-inflammatory, treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Ramathibodi Hospital
  • Chiang Mai University
  • Bamrasnaradura Infectious Diseases Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Active Comparator

Active Comparator

Arm Label

Steroid+Statin

NSAID+Statin

Steroid+Placebo

NSAID+Placebo

Arm Description

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)

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)

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

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

Outcomes

Primary Outcome Measures

Change in Clinical Symptom Score at Day 7, as measured by the 10-point visual analog scale to quantify symptom severity.
Change in serum C-reactive protein at Day 7

Secondary Outcome Measures

Days of hospitalization combined with outpatient therapeutic procedures
Study medicine discontinuation
(e.g. switching to open-label medication)
Karnofsky Performance Status Scale at day 7 and 28;
Incidence of Adverse Events
DAIDS Grading Scale 3-5 events
Radiologic improvement at 2 weeks;
Mortality
CD4 count change
Recurrence of IRIS manifestations within the 8 week study period
ART or TB therapy discontinuation
Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28

Full Information

First Posted
August 30, 2011
Last Updated
November 20, 2013
Sponsor
University of Minnesota
Collaborators
Pfizer, Minnesota Medical Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT01442428
Brief Title
Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) Treatment Trial
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 Type
Interventional

2. Study Status

Record Verification Date
November 2013
Overall Recruitment Status
Withdrawn
Why Stopped
2011 Thailand flooding led to loss of GMP pharmacy, project delays, and further regulatory challenges.
Study Start Date
January 2014 (undefined)
Primary Completion Date
March 2016 (Anticipated)
Study Completion Date
June 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Minnesota
Collaborators
Pfizer, Minnesota Medical Foundation

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Immune Reconstitution Inflammatory Syndrome, Immune Reconstitution Syndrome, Tuberculosis, HIV-infection/Aids
Keywords
TB, AIDS, HIV, IRIS, immune reconstitution inflammatory syndrome, anti-inflammatory, treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Factorial Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Steroid+Statin
Arm Type
Experimental
Arm Description
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)
Arm Title
NSAID+Statin
Arm Type
Active Comparator
Arm Description
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)
Arm Title
Steroid+Placebo
Arm Type
Active Comparator
Arm Description
Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Placebo
Arm Title
NSAID+Placebo
Arm Type
Active Comparator
Arm Description
Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week; Placebo
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
decadron
Intervention Description
Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Other Intervention Name(s)
Lipitor
Intervention Description
Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)
Intervention Type
Drug
Intervention Name(s)
Naproxen
Other Intervention Name(s)
naproxen sodium, Aleve, Anaprox, Antalgin, Feminax Ultra, Flanax, Inza, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Proxen, Synflex, Xenobid
Intervention Description
Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Atorvastatin placebo
Primary Outcome Measure Information:
Title
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
Title
Change in serum C-reactive protein at Day 7
Time Frame
Day 7
Secondary Outcome Measure Information:
Title
Days of hospitalization combined with outpatient therapeutic procedures
Time Frame
56 days
Title
Study medicine discontinuation
Description
(e.g. switching to open-label medication)
Time Frame
28 days
Title
Karnofsky Performance Status Scale at day 7 and 28;
Time Frame
Day 7 and Day 28
Title
Incidence of Adverse Events
Description
DAIDS Grading Scale 3-5 events
Time Frame
56 days
Title
Radiologic improvement at 2 weeks;
Time Frame
14 days
Title
Mortality
Time Frame
56 days
Title
CD4 count change
Time Frame
28 days
Title
Recurrence of IRIS manifestations within the 8 week study period
Time Frame
56 days
Title
ART or TB therapy discontinuation
Time Frame
56 days
Title
Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28
Time Frame
Day 28

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sasisopin Kiertiburanakul, MD, MHS
Organizational Affiliation
Mahidol University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
David R Boulware, MD, MPH
Organizational Affiliation
University of Minnesota
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Ubonvan Jongwutiwes, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Study Director
Facility Information:
Facility Name
Ramathibodi Hospital
City
Bangkok
Country
Thailand
Facility Name
Chiang Mai University
City
Chiang Mai
Country
Thailand
Facility Name
Bamrasnaradura Infectious Diseases Institute
City
Nonthaburi
Country
Thailand

12. IPD Sharing Statement

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

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