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

Tuberculosis Clinical 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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01442428
• Other study ID #: WS967180
• Status: Withdrawn
• Phase: Phase 2/Phase 3
• First received: August 30, 2011
• Last updated: November 20, 2013
• Start date: January 2014
• Est. completion date: June 2016

Study information

• Verified date: November 2013
• Source: University of Minnesota - Clinical and Translational Science Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Thailand: Ethical CommitteeUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• Dexamethasone
Dexamethasone: 4 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
• Atorvastatin
Atorvastatin: 80 mg once daily (equivalent to 30mg ± 10mg with rifamycin co-administration in this TB population)
• Naproxen
Naproxen: 250 mg 3x daily for 2 weeks, then 2x daily for 1 week, then once daily for 1 week
• Placebo
Atorvastatin placebo

Locations

Country	Name	City	State
Thailand	Ramathibodi Hospital	Bangkok
Thailand	Chiang Mai University	Chiang Mai
Thailand	Bamrasnaradura Infectious Diseases Institute	Nonthaburi

Sponsors (3)

Lead Sponsor	Collaborator
University of Minnesota - Clinical and Translational Science Institute	Minnesota Medical Foundation, Pfizer

Country where clinical trial is conducted

Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Clinical Symptom Score at Day 7, as measured by the 10-point visual analog scale to quantify symptom severity.		Day 7	No
Primary	Change in serum C-reactive protein at Day 7		Day 7	No
Secondary	Days of hospitalization combined with outpatient therapeutic procedures		56 days	No
Secondary	Study medicine discontinuation	(e.g. switching to open-label medication)	28 days	Yes
Secondary	Karnofsky Performance Status Scale at day 7 and 28;		Day 7 and Day 28	No
Secondary	Incidence of Adverse Events	DAIDS Grading Scale 3-5 events	56 days	Yes
Secondary	Radiologic improvement at 2 weeks;		14 days	No
Secondary	Mortality		56 days	Yes
Secondary	CD4 count change		28 days	Yes
Secondary	Recurrence of IRIS manifestations within the 8 week study period		56 days	No
Secondary	ART or TB therapy discontinuation		56 days	Yes
Secondary	Incidence of sputum acid fast bacilli (AFB) smear positivity at day 28		Day 28	Yes