Testing New Strategies for Patients Hospitalised With HIV-associated Disseminated Tuberculosis (NEW-STRAT TB)

March 30, 2022 updated by: Charlotte Schutz, University of Cape Town

The New Strat-TB trial is a superiority Phase III randomised control clinical trial with a 2X2 factorial design. The main aim of the study is to assess the efficacy and safety of high dose rifampicin and levofloxacin for 14 days in addition to standard TB therapy with or without steroids among adults hospitalized with HIV-associated disseminated tuberculosis.

The investigators hypothesize that intensified treatment with increased rifampicin doses at 35 mg/kg plus levofloxacin will more rapidly reduce the mycobacterial load. The investigators also hypothesize that steroids will have an immune-modulatory effect and dampen the activation of the innate immune system. The investigators hypothesize that these two strategies will lead to improved survival in patients hospitalized with HIV-associated disseminated tuberculosis.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Primary efficacy endpoint:

All-cause mortality at 12 weeks

Secondary efficacy endpoint:

All-cause mortality at 2 and 24 weeks

Safety and tolerability endpoints:

  • Occurrence of hepatotoxicity using the American Thoracic Society (ATS) hepatotoxicity criteria: Alanine aminotransferase (ALT) elevation of more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice or five times the upper limit of normal in the absence of symptoms.
  • Corticosteroid-associated adverse events, classified by severity and relation to study drug and will be reported if these develop within 4 weeks of enrolment. These will include new hypertension, new poor blood pressure control in a known hypertensive, hyperglycaemia, hypomania, mania, depression, acne, gastritis symptoms, upper gastrointestinal bleeding, and avascular bone necrosis.
  • Laboratory safety data (Grade 3 and 4 abnormalities using the ACTG grading system): liver function tests (alanine and aspartate aminotransferase[ALT, AST], gammaglutamyl transferase [GGT], alkaline phosphatase [ALP], International Normalized Ratio [INR], conjugated and total bilirubin [CBR, TBR]), glucose, full blood counts (including white cell, neutrophil and platelet counts plus haemoglobin) and electrolytes (sodium, potassium) and creatinine.
  • Occurrence of other opportunistic infections (AIDS-related, bacterial, fungal and viral) and malignancies (Kaposi's sarcoma) up to 12 weeks.
  • Occurrence of paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) in patients starting antiretroviral therapy up to 12 weeks.
  • All grade 3 and 4 clinical adverse events (using the ACTG grading system)
  • Serious adverse events
  • Adverse events requiring study drug interruption and or withdrawal
  • Adverse drug reactions attributed to study drug

Follow-up:

Participants will be followed up daily while admitted to hospital for assessment of adverse events. Safety and routine blood tests will be done on day 2, 4, 7, 14 and 28. Further visits will be on week 12 and 24.

Data monitoring:

The trial will be monitored by an independent Data and Safety Monitoring Board (DSMB) comprising 4 independent researchers and an independent statistician. If there is evidence of harm related to study medication or trial conduct the DSMB may advise the sponsor that trial enrolment should be stopped.

Clinical trial site:

Mitchells Plain Hospital and Khayelitsha Hospital

Study Type

Interventional

Enrollment (Anticipated)

732

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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
  • HIV infection

  • Disseminated TB confirmed by one or more of the following tests being positive

    1. Lysed blood Xpert Ultra positive for MTB
    2. Concentrated urine Xpert Ultra positive for MTB
    3. Urine Alere LAM positive
  • Hospital clinical team made decision to initiate TB treatment

Exclusion Criteria:

  • Pregnant or breastfeeding
  • Active or recent SARS-CoV-2 infection
  • TB treatment within the last 1 month or more than 2 doses of TB treatment
  • Rifampicin resistance
  • Neurological TB
  • Receiving corticosteroids or other immunosuppressive therapy
  • ALT >120 IU/L or total bilirubin >34 μmol/L
  • Plasma CrAg positive or cryptococcal meningitis
  • Current malignancy requiring active treatment (including any Kaposi sarcoma lesions)
  • Patients established on ART with Protease Inhibitor based regimen who cannot be switched to a dolutegravir based regimen
  • Diabetic ketoacidosis or Hyperosmolar Non-ketotic acidosis
  • Any condition in the opinion of the investigator for which participation would increase risk to the patient

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: High dose Rifampicin plus Levofloxacin
Standard TB treatment plus additional Rifampicin 35 mg/kg/day PLUS Levofloxacin for 14 days
Drug: Rifampin
Rifampicin up to 35 mg/kg/day for 14 days
Other Names:
  • Rimactane
  • Rifadin
  • rifampicin
Drug: Levofloxacin
Levofloxacin 750mg daily (for weight <50kg) or 1 g daily (for weight >50 kg) daily for 14 days
Drug: Rifampicin, Pyrazinamide, Ethambutol and Isoniazid
Rifampicin 10 mg/kg; Isoniazid 5 mg/kg; Pyrazinamide 15 mg/kg; Ethambutol15 mg/kg in fixed dose combination administered per weight band. Standard of care control arm
Other Names:
  • Rifafour
Experimental: Prednisone
Prednisone 1.5 mg/kg for 14 days
Drug: Prednisone
Prednisone 1.5mg/kg/day for 14 days
Other Names:
  • Trolic
Active Comparator: Standard TB treatment
High dose rifampicin/levofloxacin comparator
Drug: Rifampicin, Pyrazinamide, Ethambutol and Isoniazid
Rifampicin 10 mg/kg; Isoniazid 5 mg/kg; Pyrazinamide 15 mg/kg; Ethambutol15 mg/kg in fixed dose combination administered per weight band. Standard of care control arm
Other Names:
  • Rifafour
Placebo Comparator: Placebo
Prednisone comparator
Drug: Placebo
Placebo identical to Prednisone

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
All-cause mortality
Time Frame: 12 weeks
12 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
In-hospital mortality during index admission
Time Frame: 7 days
7 days
All-cause mortality
Time Frame: 2 and 24 weeks respectively
2 and 24 weeks respectively

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Cape Town

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 11, 2021

Primary Completion (Anticipated)

June 30, 2024

Study Completion (Anticipated)

December 31, 2024

Study Registration Dates

First Submitted

June 30, 2021

First Submitted That Met QC Criteria

June 30, 2021

First Posted (Actual)

July 7, 2021

Study Record Updates

Last Update Posted (Actual)

March 31, 2022

Last Update Submitted That Met QC Criteria

March 30, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HREC REF: 001/2021

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

IPD will be shared on request, after discussion with ethics committee

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)
  • Analytic Code

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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