Prevention of Early Mortality by Presumptive Tuberculosis (TB) Treatment (PrOMPT)

Prevention of Early Mortality by Presumptive TB Treatment in HIV-infected Patients Initiating Antiretroviral Therapy

This study investigates the prevention of early mortality in patients initiating antiretroviral therapy (ART) in sub-Saharan Africa where 79% of the co-infected cases of TB reside. Many published studies have shown a surprisingly high proportion of all patients initiated on ART dying within 6 months (8-26%) with increasing risk with decreasing CD4 T cell count. The majority (median 70%) occur in the first 3 months with the greatest proportion of deaths due to previously undiagnosed tuberculosis (TB). The investigators will enroll patients from 4 geographically diverse countries (Gabon, Mozambique, South Africa, and Uganda) in a randomized open label clinical trial targeting a population of people with high mortality risk; patients with CD4 T cell count < 50 cells/μl and body mass index (BMI) < 18 kg/m2. Severely immunocompromised patients with low BMI in the intervention arm will receive presumptive anti-TB 4-drug chemotherapy and subsequently initiate ART within 2 weeks compared to ART alone. The main objective is to measure and compare early mortality in the group presumptively treated for TB in addition to ART. Other sub-objectives are to determine the predictors of early mortality and the causes of death by autopsy (traditional and verbal), to determine if presumptive anti-TB treatment affects viral suppression with ART, and to assess incidence rates and characterize drug toxicity in patients dually treated. Because of the high rates of TB co-infection in sub-Saharan Africa in the HIV-infected, the investigators expect that patients presumptively treated for TB in addition to HIV will have a lower mortality rate than patients receiving ART only. This trial is expected to be of great public health benefit and generalisability.

Study Overview

• Status: Terminated
• Conditions: HIV Infection; Tuberculosis
• Intervention / Treatment: Drug: Experimental: Empiric TB treatment; Drug: ART only arm

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 4

Contacts and Locations

Study Locations

• Gabon
  • Lambaréné, Gabon
    • Medical Research Unit, Albert Schweitzer Hospital
• Mozambique
  • Beira, Mozambique
    • Ministry of Health -Provincial Heatlh Directorate of the Sofala Province (Direcção Provincial de Saúde de Sofala DPSS)
• Uganda
  • Kampala, Uganda
    • Infectious Diseases Institute University Makarere

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged > 18 years old
• HIV-1 positive
• Eligible for antiretroviral treatment with CD4 T cell count < 50 cells/μl
• BMI < 18

Exclusion Criteria:

• Patients with smear-positive pulmonary TB
• Patients who fulfill the diagnostic criteria for smear-negative pulmonary or extrapulmonary TB (http://www.who.int/tb/publications/2006/tbhiv_recommendations.pdf ).
• Previous TB treatment (history of TB medication for > 1 month
• History of using antiretroviral drugs
• Symptomatic known underlying liver disease or transaminases > 5x upper limit of normal
• Known or suspected drug resistance to more than one first-line TB drug according to WHO criteria but excluding HIV infection (e.g. household contacts of MDRTB patients)
• Pregnant or breast-feeding
• Patients with cryptococcal meningitis (CrAG positive with neurologic symptoms)
• Patients with other severe (opportunistic) disease such as disseminated KS, malignant lymphoma, toxoplasmosis who may not be able to tolerate anti-TB medication or require other specific therapy
• Patients with danger signs (respiratory rate > 30 per minute, heart rate > 120bpm, temperature > 39oC, and unable to ambulate)
• Taking other potentially life-saving medications (e.g. for other OIs, or immunosuppressants) that are incompatible with anti-TB chemotherapy or ART
• Unable to swallow TB medications
• Unable to follow-up at the clinic for regularly scheduled follow-up (e.g. too far from clinic)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empiric TB treatment; Empiric initiation of 4 drug TB treatment (8 weeks of 4 drug, 16 weeks of 2 drug therapy) followed by ART (efavirenz-based) within 2 weeks	Drug: Experimental: Empiric TB treatment; Initiation of 4 drug TB treatment (8 weeks of 4 drug, 16 weeks of 2 drug therapy) followed by ART (efavirenz-based) within 2 weeks
Active Comparator: ART only arm; ART (efavirenz-based) only (+ pyridoxine 50mg) given within 2 weeks after enrolment	Drug: ART only arm; ART (efavirenz-based) only (+ pyridoxine 50mg) given within 2 weeks after enrolment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
All-cause mortality in the first 24 weeks after initiation of ART	24 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
CD4 T cell absolute increase	24 weeks
Causes of death	24 weeks
Safety and tolerability of anti-tuberculous medications	24 weeks
HIV viral suppression	24 weeks
TB incidence rates after ART initiation	24 weeks

Collaborators and Investigators

• Sponsor: Prof JMA Lange
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP)
• Investigators: Study Director: Frank Cobelens, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Principal Investigator: Yuka Manabe, Infectious Diseases Institute at Makerere University

Publications and helpful links

Helpful Links

• Official Website of the sponsor

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: July 25, 2011
• First Submitted That Met QC Criteria: August 15, 2011
• First Posted (Estimate): August 16, 2011

Study Record Updates

• Last Update Posted (Estimate): February 17, 2014
• Last Update Submitted That Met QC Criteria: February 14, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: TB
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: AIGHD_001