TB-IRIS NSAID Cox-2 Inhibitor Prevention Trial

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Abstract

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

Dates

Last Verified:	03/31/2014
First Submitted:	02/06/2014
Estimated Enrollment Submitted:	02/06/2014
First Posted:	02/10/2014
Last Update Submitted:	04/01/2014
Last Update Posted:	04/02/2014
Actual Study Start Date:	03/31/2014
Estimated Primary Completion Date:	03/31/2015
Estimated Study Completion Date:	03/31/2015

Condition or disease

Tuberculosis

Intervention/treatment

Drug: Meloxicam 7.5 mg once-daily

Phase

Phase 3

Arm Groups

Arm	Intervention/treatment
Placebo Comparator: Placebo 7.5 mg daily for 8 weeks Placebo 7.5 mg once-daily First 8 weeks of ART Only Control arm
Experimental: Meloxicam 7.5 mg once-daily Meloxicam 7.5mg once-daily for 8 weeks	Drug: Meloxicam 7.5 mg once-daily Meloxicam 7.5mg daily for 8 weeks

Eligibility Criteria

Ages Eligible for Study	18 Years To 18 Years
Sexes Eligible for Study	All
Accepts Healthy Volunteers	Yes
Criteria	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

Outcome

Primary Outcome Measures

1. Incidence of TB IRIS [6 months]

Secondary Outcome Measures

1. Proportion discontinuing Meloxicam due to adverse event [6 months]

2. 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]

3. 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]

TB-IRIS NSAID Cox-2 Inhibitor Prevention Trial

Keywords

cyclooxygenase

prostaglandin

prostaglandin f 2 alpha

tuberculosis

abscess

suppuration

sarcoma

dyspepsia

fibrosis

inflammation

cystic fibrosis

meningitis

anti inflammatory