TB-IRIS NSAID Cox-2 Inhibitor Prevention Trial

Study Overview
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Brief Summary
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Background: Non-Steroid Anti-Inflammatory Drugs (NSAIDs) reduce pain and inflammation by inhibiting cyclooxygenase, an enzyme in the pathway for formation of prostaglandins and thromboxane. Prior studies have proven the role of ibuprofen (an NSAID) in modulating lung injury and decreasing pulmonary damage in cystic fibrosis. While there has been an intense effort by the scientific community to define the best treatment strategies for tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS), to our knowledge there is no available study evaluating preventive strategies using anti-inflammatory agents for TB-IRIS, a highly morbid complication in HIV-infected TB patients initiating antiretroviral therapy (ART). Design and Methods: We propose to conduct a single center double-blind placebo-controlled randomized trial to investigate the efficacy of daily self-administered Meloxicam (a NSAID) versus placebo for prevention of Tuberculosis associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS). A total of 150 HIV-infected adults who are treated for Tuberculosis for at least 2 weeks and about to initiate HIV treatment at Brewelskloof Hospital, Worcester, and Tygerberg Teaching Hospital, Cape Town, will be randomized to one of the following treatments: Meloxicam 7.5 mg tablet once-a-day, the experimental arm, versus Placebo tablet once-a-day, the control arm, for 8 weeks. All patients will be followed up for 12 months. Primary efficacy outcome: The decrease of the incidence of paradoxical TB IRIS by at least 20%; Primary safety outcome: The proportion of patients who temporarily or permanently discontinue Meloxicam due to any adverse event (e.g. dyspepsia or gastro-intestinal upset). Secondary outcomes are: 1) the proportion of patients in each arm with the following indicators of TB-IRIS severity/quality of life (QOL) (degree of pain or discomfort >III, presence of local or disseminated suppuration/abscess of any site, unscheduled clinic visits, hospitalizations, missed more than a day at work, etc; 2) The incidence of other types of IRIS (e.g. Kaposi Sarcoma or cryptococcal meningitis). This study will provide important and novel data on the feasibility and efficacy of using a cheap, widely available NSAID used in both developed and developing countries, as a preventive intervention for TB-IRIS that could be quickly put into practice if proven to be effective

Official Title
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A Double-Blind Randomized Placebo Controlled Trial for Prevention of Tuberculosis-Immune Reconstitution Inflammatory Syndrome With Non-Steroid Anti-Inflammatory Drugs (NSAIDs) in HIV-Infected Adults

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Meloxicam 7.5mg daily for 8 weeks


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and non-pregnant females age 18 years of age or older Evidence of HIV-1 infection TB treatment (<2 weeks) and initiating EFV-based antiretroviral therapy as per the South African Department of Health Guidelines Living in the study site catchment area and having had a known address for more than 3 months Written informed consent Exclusion Criteria: History of aspirin sensitivity and allergies to other NSAIDs Current or recent use (<3 months) of aspirin, NSAIDs, or anticoagulants such as warfarin. Current or recent use of corticosteroid therapy History of gastro-intestinal bleeding or peptic ulcer History of cardiovascular thrombotic events (myocardial infarction or stroke), hypertension, or congestive heart failure Severe renal impairment as evidenced by creatinine clearance <50 (Cockcroft- Gault Formula) Severe liver disease (ALT > five times upper limit of normal) Presence of a medical condition likely to result in death within 6 months from start of ART. These conditions include suspected or CNS lymphoma, PMLE and disseminated visceral Kaposi's sarcoma Cognitive disorder(s) that could impair ability to comply with study requirements, as determined by the study physician Karnofsky performance score <60

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo 7.5 mg daily for 8 weeks<br>Placebo 7.5 mg once-daily First 8 weeks of ART Only Control arm | |
| Experimental: Meloxicam 7.5 mg once-daily<br>Meloxicam 7.5mg once-daily for 8 weeks | Drug: Meloxicam 7.5mg daily for 8 weeks<br>* Meloxicam 7.5mg daily for 8 weeks<br>* Other names: Cox-2 Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of TB IRIS |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion discontinuing Meloxicam due to adverse event |  | 6 months | 
| The proportion of patients in each arm with the following indicators of TB-IRIS severity/quality of life (QOL) (degree of pain or discomfort >III |  | 6 months | 
| The proportion of patients with local or disseminated suppuration/abscess of any site, unscheduled clinic visits, hospitalizations, missed more than a day at work, etc |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TB, IRIS