Clinical Trial: Preventing TB-IRIS in High-risk Patients: a Randomized Placebo-controlled Trial of Prednisone
Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional
Official Title: Preventing Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome in High-risk Patients: a Randomized Placebo-controlled Trial of Prednisone
Brief Summary: Tuberculosis (TB) is the most common opportunistic infection amongst HIV-infected patients starting antiretroviral therapy (ART) in developing countries and thus the most frequent form of immune reconstitution inflammatory syndrome (IRIS). Paradoxical TB-IRIS occurs in 8- 43% of patients starting ART while on TB treatment and results in morbidity, hospitalisation, consumes health care resources and TB-IRIS may be fatal. We have previously demonstrated in a clinical trial that prednisone reduces morbidity when used for treatment of paradoxical TB-IRIS. This trial is a double-blind placebo-controlled trial of prophylactic prednisone (40mg/day for 2 weeks followed by 20mg/day for 2 weeks, started on the same day as ART) in patients with TB who are identified as being at high risk for paradoxical TB-IRIS (starting ART within 30 days of initiating TB treatment and CD4 < 100/μL). The trial will enroll 240 participants, randomised 1:1 (prednisone:placebo). The primary endpoint is development of paradoxical TB-IRIS, defined using international consensus case definitions. Secondary endpoints include time to IRIS event, severity of IRIS, quality of life assessment, mortality and corticosteroids adverse events. The trial is powered to determine a reduction in TB-IRIS events.
Detailed Summary:
Objective: To determine whether the addition of prednisone to the first 4 weeks of antiretroviral therapy (ART) reduces the risk of paradoxical TB-IRIS in HIV-infected patients being treated for TB who are at high risk of developing TB-IRIS (CD4 <100 cells/μl and starting ART within 30 days of TB treatment).
Design: A randomized double-blind placebo-controlled trial to evaluate the incidence of paradoxical TB-IRIS over the first 12 weeks of ART in participants who receive a 4 week course of prednisone versus participants who receive a 4 week course of placebo.
Primary efficacy endpoint:
The development of paradoxical TB-IRIS within 12 weeks of starting ART (defined using the International Network for the Study of HIV-associated IRIS (INSHI) consensus case definition).
Secondary efficacy endpoints:
- Time to IRIS event
- Severity of IRIS events (defined by the following: need for hospitalisation for IRIS, C-reactive protein, and neurological involvement)
- Duration of TB-IRIS event (from onset of symptoms/signs to resolution of TB-IRIS symptoms/signs)
- Mortality attributed to TB and TB-IRIS
- All-cause mortality
- Composite endpoint of death, hospitalization, or hepatotoxicity (using the protocol-specified definition of Grade 3 or 4 increase in ALT or bilirubin).
- Other (non-TB) IRIS events
- Quality of life assessment (measured using PROQOL-HIV, EQ-5D-3L, HIV symptom index and Karnofsky score)
- The development of paradoxical TB-IRIS within 12 weeks of starting ART (defined using the International Network for the Study of HIV-associated IRIS (INSHI) consensus case definition)
Original Primary Outcome: Same as current
Current Secondary Outcome:
- Time to IRIS event [ Time Frame: 12 weeks ]
- Severity of IRIS events [ Time Frame: 12 weeks ]Defined by the following: need for hospitalisation for IRIS, C-reactive protein, and neurological involvement
- Duration of TB-IRIS event [ Time Frame: Average 8-12 weeks from onset ]From onset of symptoms/signs to resolution of TB-IRIS symptoms/signs. Participants will be followed until resolution of TB-IRIS symptoms/signs which is an average 8-12 weeks from onset.
- Mortality attributed to TB and TB-IRIS [ Time Frame: 12 weeks ]
- All-cause mortality [ Time Frame: 12 weeks ]
- Composite endpoint of death, hospitalization, or hepatotoxicity (using the protocol-specified definition of Grade 3 or 4 increase in ALT or bilirubin) [ Time Frame: 12 weeks ]
- Other (non-TB) IRIS events [ Time Frame: 12 weeks ]Number of other IRIS events (other than TB-IRIS) occurring in participants
- Adverse events and severe adverse events ascribed to TB treatment, ART or co-trimoxazole [ Time Frame: 12 weeks ]This will include a pre-specified analysis of drug-induced liver injury and drug rash. This assessment will include the number of treatment interruptions for drug adverse events.
- Discontinuation of either ART or TB treatment for > 5 days due to adverse events [ Time Frame: 12 weeks ]
- Number of hospitalizations [ Time Frame: 12 weeks ]
- Corticosteroid-associated adverse events, classified by severity and relation to study drug [ Time Frame: 12 weeks ]These will include hypertension, hyperglycaemia, hypomania/mania, depression, acne, epigastric pain, upper gastro-intestinal bleeding, Cushingoid features, new oedema and avascular bone necrosis
- Laboratory safety data: Glucose [ Time Frame: 12 weeks ]
- Other infections (AIDS-related, bacterial, fungal and viral) and malignancies (Kaposi's sarcoma) [ Time Frame: 12 weeks ]
- All grade 1, 2, 3 and 4 adverse events (clinical and laboratory using the ACTG grading system) [ Time Frame: 12 weeks ]
- Total number of days hospitalised [ Time Frame: 12 weeks ]
- Laboratory safety data: Haemoglobin [ Time Frame: 12 weeks ]
- Laboratory safety data: White cell count [ Time Frame: 12 weeks ]
- Laboratory safety data: Serum sodium [ Time Frame: 12 weeks ]
- Laboratory safety data: Serum potassium [ Time Frame: 12 weeks ]
Original Secondary Outcome: Same as current
Information By: University of Cape Town
Dates:
Date Received: August 12, 2013
Date Started: August 2013
Date Completion: April 2017
Last Updated: December 15, 2016
Last Verified: December 2016
