Preventing Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome in High-risk Patients: a Randomized Placebo-controlled Trial of Prednisone (Pred-ART)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by University of Cape Town
Sponsor:
Collaborators:
Institute of Tropical Medicine, Antwerp, Belgium
Imperial College London, United Kingdom
European and Developing Countries Clinical Trials Partnership (Funder)
South African Department of Science and Technology (Funder)
Information provided by (Responsible Party):
Graeme Meintjes, University of Cape Town
ClinicalTrials.gov Identifier:
NCT01924286
First received: August 12, 2013
Last updated: September 12, 2013
Last verified: September 2013
  Purpose

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 Intervention Phase
HIV Associated Tuberculosis
Drug: Prednisone
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by University of Cape Town:

Primary Outcome Measures:
  • Development of paradoxical TB-IRIS [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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:
  • Time to IRIS event [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Severity of IRIS events [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • All-cause mortality [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Other (non-TB) IRIS events [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • Number of hospitalizations [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • Corticosteroid-associated adverse events, classified by severity and relation to study drug [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
  • Other infections (AIDS-related, bacterial, fungal and viral) and malignancies (Kaposi's sarcoma) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • All grade 1, 2, 3 and 4 adverse events (clinical and laboratory using the ACTG grading system) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • Total number of days hospitalised [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • Laboratory safety data: Haemoglobin [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • Laboratory safety data: White cell count [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • Laboratory safety data: Serum sodium [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • Laboratory safety data: Serum potassium [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • Quality of life assessment [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Quality of life assessment (measured using PROQOL-HIV)

  • Quality of life assessment [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Measured using EQ-5D-3L

  • Quality of life assessment [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Measured using HIV symptom index

  • Quality of life assessment [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Measured using Karnofsky score


Estimated Enrollment: 240
Study Start Date: August 2013
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prednisone
Prednisone oral tablets 40mg daily for 2 weeks followed by 20mg daily for 2 weeks
Drug: Prednisone
Placebo Comparator: Placebo
Placebo oral tablets 40mg daily for 2 weeks followed by 20mg daily for 2 weeks
Drug: Placebo

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 aminotranferase > 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01924286

Contacts
Contact: Graeme Meintjes, MD MPH PhD +27214066075 graeme.meintjes@uct.ac.za
Contact: Charlotte Schutz, MD MPH +27214066797 charlottelouw@discoverymail.co.za

Locations
South Africa
Site B Khayelitsha HIV/TB clinic Recruiting
Cape Town, Western Cape, South Africa, 7784
Contact: Shaheed Mattee, MD    27 21 364 9836    shahmat@vodamail.co.za   
Principal Investigator: Graeme Meintjes, MD MPH PhD         
Sub-Investigator: Charlotte Schutz, MD MPH         
Sub-Investigator: Liz Blumenthal, MD         
Sub-Investigator: Shaheed Mattee, MD         
Sub-Investigator: Funeka Bango, MD         
Sub-Investigator: Jan Kuehne, MD         
Sponsors and Collaborators
University of Cape Town
Institute of Tropical Medicine, Antwerp, Belgium
Imperial College London, United Kingdom
European and Developing Countries Clinical Trials Partnership (Funder)
South African Department of Science and Technology (Funder)
Investigators
Principal Investigator: Graeme Meintjes, MD MPH PhD University of Cape Town
  More Information

Additional Information:
No publications provided

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, DOH-27-0813-4336
Study First Received: August 12, 2013
Last Updated: September 12, 2013
Health Authority: South Africa: Medicines Control Council

Keywords provided by University of Cape Town:
HIV, tuberculosis, antiretroviral therapy, glucocorticoids, prednisone, prevention, immune reconstitution inflammatory syndrome

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

ClinicalTrials.gov processed this record on October 20, 2014