A randomised controlled trial of prednisone versus placebo in the management of human immunodeficiency virus (HIV)-infected patients presenting with mild to moderate Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome after commencing Highly Active Antiretroviral Therapy

ISRCTN	ISRCTN21322548
DOI	https://doi.org/10.1186/ISRCTN21322548
Protocol serial number	TB-IRIS-RCT
Sponsor	University of Cape Town - Research Ethics Committee, Faculty of Health Sciences (South Africa)
Funder	Medical Research Council, South Africa (no reference number provided)

Submission date: 03/06/2005
Registration date: 17/08/2005
Last edited: 17/08/2012

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Gary Maartens
Scientific

Division of Pharmacology
University of Cape Town Medical School
K45
Old Main Building
Groote Schuur Hospital
Cape Town
7925
South Africa

Study information

Primary study design	Interventional
Study design	Randomised placebo-controlled trial
Secondary study design	Randomised controlled trial
Scientific title
Study acronym	TB-IRIS-RCT
Study objectives	We propose a randomised placebo-controlled trial of prednisone as an adjunct in the management of HIV-infected patients with mild to moderate Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS). This syndrome manifests as a paradoxical worsening of clinical features of tuberculosis after commencing Highly Active Antiretroviral Therapy (HAART). We hypothesise a reduction in the requirement for hospitalisation and therapeutic procedures among patients receiving prednisone.
Ethics approval(s)	Not provided at time of registration
Health condition(s) or problem(s) studied	HIV and Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome
Intervention	Randomization to oral prednisone 1.5 mg/kg for 2 weeks followed by 0.75 mg/kg for 2 weeks or identical placebo medication.
Intervention type	Drug
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Prednisone
Primary outcome measure(s)	Combined hospitalisation and procedures endpoint (cumulative duration of hospitalisation in days + outpatient therapeutic procedures counted as one day)
Key secondary outcome measure(s)	Radiological Endpoints: A significant improvement in radiological manifestations of IRIS: 1. For Chest X Ray pulmonary infiltrates, a significant reduction in composite infiltrate score (6 zones each measured for degree of infiltrate by Radiologist to give composite score) 2. For large nodes noted on the Chest X Ray, a significant reduction in size 3. For computed tomography (CT) scans, a significant reduction in infiltrate or node size 4. For peripheral & abdominal nodes, a significant reduction in volume as measured by ultrasound 5. For cold abscesses, a significant reduction in volume as measured by ultrasound Other Secondary Endpoints: 1. 50% reduction in symptom score (Wilson 2004) 2. A significant improvement in the Quality of Life MOS-HIV score 3. Improvement in Karnofsky score of greater than 10 4. Corticosteroid side effects a. New onset of diabetes b. New onset of hypertension c. Psychological side effects d. Onset of new opportunistic infection/cancer such as Kaposis sarcoma, Herpes simplex lesions, Herpes zoster lesions 5. 50% reduction in C-Reactive Protein (CRP) value 6. Weight gain 7. Mortality 8. The need to stop HAART, TB therapy or study drug 9. Adherence with HAART and study drug as assessed by pill count and adherence with TB treatment as assessed by TB clinic card assessment 10. Recurrence of IRIS manifestations within the 12 week study period 11. In patients with an Alkaline Phosphatase or gamma glutamyl transpeptidase (GGT) that was elevated more than 2 x upper limit of normal (ULN) at baseline, a reduction of 50% from the baseline value 12. CD4 and Viral load 13. For ascites, reduction in abdominal girth
Completion date	31/05/2007

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	100
Key inclusion criteria	A. Age 18 years and over B. Informed consent (written) C. Prior to the introduction of HAART the following criteria must be met for the diagnosis of TB-IRIS to be considered: 1. The patient has HIV infection 2. The patient should be antiretroviral-naïve (excluding receipt of antiretroviral treatment within mother to child transmission programmes Nevirapine single-dose with or without Zidovudine in the third trimester) 3. The patient has microbiologic, histologic or very strong clinical evidence of tuberculosis 4. There has been a documented improvement in symptoms, Karnofsky score and/or weight, resolution of fever and clinical and radiological stabilization during the intensive phase of multidrug TB therapy 5. That adherence with anti-TB treatment is >80% 6. That the infecting strain of M. tuberculosis is sensitive to rifampicin, if this result is available D. Consider TB-IRIS if, within 3 months of the introduction of multi-drug HAART 1. Adherence with HAART is documented and the patient was on anti-tuberculous therapy when HAART commenced 2. There are new or recurrent constitutional symptoms PLUS one or more of: i. New or expanding lymph nodes (>20 mm or >50% in volume) ii. New or expanding tuberculous cold abscesses (e.g. paraspinal) iii. New or expanding pulmonary infiltrates (radiographically confirmed) iv. New or enlarging serous effusions (pericardial, pleural or ascitic) Patients presenting with other manifestations of TB-IRIS (e.g. central nervous system [CNS] tuberculoma) will not be included in this study.
Key exclusion criteria	1. Previous systemic steroid therapy as part of the management of tuberculosis 2. Pregnancy 3. Uncontrolled Diabetes Mellitus 4. Adrenal failure 5. Severe TB-IRIS (these cases will receive open label corticosteroids) manifested by: a. Respiratory failure (pO2 <8 kPa) b. Altered level of consciousness or new focal neurological signs c. Compression of vital structures (e.g. bronchostenosis) 6. Kaposis sarcoma
Date of first enrolment	01/06/2005
Date of final enrolment	31/05/2007

Locations

Countries of recruitment

South Africa

Study participating centre

Division of Pharmacology

Cape Town
7925
South Africa

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	15/08/2012		Yes	No