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Preventing TB-IRIS in High-risk Patients: a Randomized Placebo-controlled Trial of Prednisone (Pred-ART)

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ClinicalTrials.gov Identifier: NCT01924286
Recruitment Status : Completed
First Posted : August 16, 2013
Last Update Posted : January 19, 2018
Institute of Tropical Medicine, Belgium
Imperial College London
European and Developing Countries Clinical Trials Partnership (EDCTP)
Department of Science and Technology, South Africa
Information provided by (Responsible Party):
Graeme Meintjes, University of Cape Town

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.

Condition or disease Intervention/treatment Phase
Immune Reconstitution Inflammatory Syndrome HIV Tuberculosis Drug: Prednisone Drug: Placebo Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Preventing Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome in High-risk Patients: a Randomized Placebo-controlled Trial of Prednisone
Actual Study Start Date : August 30, 2013
Primary Completion Date : April 2016
Study Completion Date : April 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Prednisone
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Prednisone
Prednisone oral tablets 40mg daily for 2 weeks followed by 20mg daily for 2 weeks
Drug: Prednisone
Other Name: Trolic
Placebo Comparator: Placebo
Placebo oral tablets 40mg daily for 2 weeks followed by 20mg daily for 2 weeks
Drug: Placebo

Primary Outcome Measures :
  1. Development of paradoxical TB-IRIS [ Time Frame: 12 weeks ]
    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 Outcome Measures :
  1. Time to IRIS event [ Time Frame: 12 weeks ]
  2. Severity of IRIS events [ Time Frame: 12 weeks ]
    Defined by the following: need for hospitalisation for IRIS, C-reactive protein, and neurological involvement

  3. 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.

  4. Mortality attributed to TB and TB-IRIS [ Time Frame: 12 weeks ]
  5. All-cause mortality [ Time Frame: 12 weeks ]
  6. 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 ]
  7. Other (non-TB) IRIS events [ Time Frame: 12 weeks ]
    Number of other IRIS events (other than TB-IRIS) occurring in participants

  8. 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.

  9. Discontinuation of either ART or TB treatment for > 5 days due to adverse events [ Time Frame: 12 weeks ]
  10. Number of hospitalizations [ Time Frame: 12 weeks ]
  11. 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

  12. Laboratory safety data: Glucose [ Time Frame: 12 weeks ]
  13. Other infections (AIDS-related, bacterial, fungal and viral) and malignancies (Kaposi's sarcoma) [ Time Frame: 12 weeks ]
  14. All grade 1, 2, 3 and 4 adverse events (clinical and laboratory using the ACTG grading system) [ Time Frame: 12 weeks ]
  15. Total number of days hospitalised [ Time Frame: 12 weeks ]
  16. Laboratory safety data: Haemoglobin [ Time Frame: 12 weeks ]
  17. Laboratory safety data: White cell count [ Time Frame: 12 weeks ]
  18. Laboratory safety data: Serum sodium [ Time Frame: 12 weeks ]
  19. Laboratory safety data: Serum potassium [ Time Frame: 12 weeks ]

Other Outcome Measures:
  1. Quality of life assessment [ Time Frame: 12 weeks ]
    Quality of life assessment (measured using PROQOL-HIV)

  2. Quality of life assessment [ Time Frame: 12 weeks ]
    Measured using EQ-5D-3L

  3. Quality of life assessment [ Time Frame: 12 weeks ]
    Measured using HIV symptom index

  4. Quality of life assessment [ Time Frame: 12 weeks ]
    Measured using Karnofsky score

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. HIV-infected HIV infection will be confirmed by two different rapid tests (as per South African national Department of Health guidelines) and an HIV viral load test.
  2. CD4 count < 100/μL One CD4 count taken within 3 months prior to enrolment less than 100/μL will qualify, even if other CD4 counts are greater than 100/μL
  3. ART-naïve Patients who report having been treated with triple drug or dual drug ART previously will be excluded. Single dose nevirapine or short term AZT monotherapy for PMTCT is not an exclusion.
  4. Confirmed diagnosis of TB (smear, culture, Xpert MTB/RIF test or compatible histology) or strong clinical and radiological evidence of TB with symptomatic response to TB treatment
  5. On TB treatment for less than 30 days prior to study entry.
  6. Eligible for ART and patient consents to starting ART within 30 days of starting TB treatment.
  7. Written informed consent for trial

Exclusion Criteria:

  1. Kaposi's sarcoma (KS) A thorough examination for KS lesions will be performed and any suspicious lesion will be biopsied. Any history of treatment for KS will also be an exclusion.
  2. Pregnant All female participants of child-bearing potential will have a pregnancy test performed prior to enrollment and will be counseled to use to two reliable methods of contraception for the duration of the trial.
  3. <18 years old
  4. TB meningitis or tuberculoma at TB diagnosis
  5. Clinical syndrome of pericardial TB at TB diagnosis (a pericardial effusion noted on ultrasound scan alone is not an exclusion criterion)
  6. Rifampicin-resistant TB diagnosed by Xpert MTB/RIF test or a drug susceptibility test performed on a culture isolate.
  7. On corticosteroids for another indication or on any other immunosuppressive medication within the past 7 days.
  8. Uncontrolled diabetes mellitus
  9. The following abnormal laboratory values:

    Alanine aminotransferase > 200 IU/l Absolute neutrophil count < 500/mm3

  10. Not on standard intensive phase TB treatment (Rifampicin, isoniazid, pyrazinamide and ethambutol)
  11. Poor clinical response to TB treatment prior to ART as judged by the clinical investigators.
  12. Hepatitis B surface antigen positive

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01924286

South Africa
Site B Khayelitsha HIV/TB clinic
Cape Town, Western Cape, South Africa, 7784
Sponsors and Collaborators
University of Cape Town
Institute of Tropical Medicine, Belgium
Imperial College London
European and Developing Countries Clinical Trials Partnership (EDCTP)
Department of Science and Technology, South Africa
Principal Investigator: Graeme Meintjes, MD MPH PhD University of Cape Town

Additional Information:
Study Data/Documents: Statistical Analysis Plan  This link exits the ClinicalTrials.gov site

Responsible Party: Graeme Meintjes, Principal Investigator, University of Cape Town
ClinicalTrials.gov Identifier: NCT01924286     History of Changes
Other Study ID Numbers: CIDRI_001
SP.2011.41304.074 ( Other Grant/Funding Number: EDCTP )
DOH-27-0813-4336 ( Registry Identifier: South African National Health Research Ethics Council )
First Posted: August 16, 2013    Key Record Dates
Last Update Posted: January 19, 2018
Last Verified: January 2018

Keywords provided by Graeme Meintjes, University of Cape Town:
Immune reconstitution inflammatory syndrome
Highly active antiretroviral therapy
Preventive therapy

Additional relevant MeSH terms:
Immune Reconstitution Inflammatory Syndrome
Pathologic Processes
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Immune System Diseases
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents