Testing New Strategies for Patients Hospitalised With HIV-associated Disseminated Tuberculosis (NEW-STRAT TB)
Primary Purpose
Disseminated Tuberculosis, HIV
Status
Recruiting
Phase
Phase 3
Locations
South Africa
Study Type
Interventional
Intervention
Rifampin
Levofloxacin
Rifampicin, Pyrazinamide, Ethambutol and Isoniazid
Prednisone
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Disseminated Tuberculosis focused on measuring HIV, High dose rifampicin, Fluoroquinolones, Glucocorticoids, Antiretroviral therapy
Eligibility Criteria
Inclusion Criteria:
- Aged >18
- HIV infection
Disseminated TB confirmed by one or more of the following tests being positive
- Lysed blood Xpert Ultra positive for MTB
- Concentrated urine Xpert Ultra positive for MTB
- 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
Sites / Locations
- Khayelitsha Hospital, c/o Steve Biko and Walter Sisulu Drives, KhayelitshaRecruiting
- Mitchells Plain Hospital, Mitchells PLainRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Active Comparator
Placebo Comparator
Arm Label
High dose Rifampicin plus Levofloxacin
Prednisone
Standard TB treatment
Placebo
Arm Description
Standard TB treatment plus additional Rifampicin 35 mg/kg/day PLUS Levofloxacin for 14 days
Prednisone 1.5 mg/kg for 14 days
High dose rifampicin/levofloxacin comparator
Prednisone comparator
Outcomes
Primary Outcome Measures
All-cause mortality
Secondary Outcome Measures
In-hospital mortality during index admission
All-cause mortality
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04951986
Brief Title
Testing New Strategies for Patients Hospitalised With HIV-associated Disseminated Tuberculosis
Acronym
NEW-STRAT TB
Official Title
Testing New Strategies for Patients Hospitalised With HIV-associated Disseminated Tuberculosis
Study Type
Interventional
2. Study Status
Record Verification Date
March 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 11, 2021 (Actual)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cape Town
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Disseminated Tuberculosis, HIV
Keywords
HIV, High dose rifampicin, Fluoroquinolones, Glucocorticoids, Antiretroviral therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Model Description
First intervention (open label):
a) Experimental arm: Standard first-line anti-tuberculosis therapy plus additional rifampicin to reach 35mg/kg/day for 14 days plus levofloxacin 750mg/day for weight <50kg and 1g/day for weight >50kg for 14 days b) Control arm: Standard TB therapy containing rifampicin 10mg/kg for 14 days (standard of care) After 14 days both study arms will continue standard TB therapy with rifampicin at 10mg/kg to complete 2 months of intensive phase in total. This will be followed by standard continuation phase TB therapy.
2. Second intervention (double-blind):
Experimental arm: Prednisone 1.5mg/kg per day for 14 days
Control arm: Identical placebo for 14 days
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
732 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
High dose Rifampicin plus Levofloxacin
Arm Type
Experimental
Arm Description
Standard TB treatment plus additional Rifampicin 35 mg/kg/day PLUS Levofloxacin for 14 days
Arm Title
Prednisone
Arm Type
Experimental
Arm Description
Prednisone 1.5 mg/kg for 14 days
Arm Title
Standard TB treatment
Arm Type
Active Comparator
Arm Description
High dose rifampicin/levofloxacin comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Prednisone comparator
Intervention Type
Drug
Intervention Name(s)
Rifampin
Other Intervention Name(s)
rifampicin, Rifadin, Rimactane
Intervention Description
Rifampicin up to 35 mg/kg/day for 14 days
Intervention Type
Drug
Intervention Name(s)
Levofloxacin
Intervention Description
Levofloxacin 750mg daily (for weight <50kg) or 1 g daily (for weight >50 kg) daily for 14 days
Intervention Type
Drug
Intervention Name(s)
Rifampicin, Pyrazinamide, Ethambutol and Isoniazid
Other Intervention Name(s)
Rifafour
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Prednisone
Other Intervention Name(s)
Trolic
Intervention Description
Prednisone 1.5mg/kg/day for 14 days
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo identical to Prednisone
Primary Outcome Measure Information:
Title
All-cause mortality
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
In-hospital mortality during index admission
Time Frame
7 days
Title
All-cause mortality
Time Frame
2 and 24 weeks respectively
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Aged >18
HIV infection
Disseminated TB confirmed by one or more of the following tests being positive
Lysed blood Xpert Ultra positive for MTB
Concentrated urine Xpert Ultra positive for MTB
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Charlotte Schutz, PhD
Phone
+27 (0)21 406 6797
Email
charlotte.schutz@uct.ac.za
Facility Information:
Facility Name
Khayelitsha Hospital, c/o Steve Biko and Walter Sisulu Drives, Khayelitsha
City
Cape Town
State/Province
Western Cape
ZIP/Postal Code
7784
Country
South Africa
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charlotte Schutz, PhD
Email
charlotte.schutz@uct.ac.za
First Name & Middle Initial & Last Name & Degree
Phiona Namale, MBChB
Email
Phiona.namale@uct.ac.za
Facility Name
Mitchells Plain Hospital, Mitchells PLain
City
Cape Town
State/Province
Western Cape
ZIP/Postal Code
7785
Country
South Africa
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charlotte Schutz, PhD
Email
Charlotte.Schutz@uct.ac.za
First Name & Middle Initial & Last Name & Degree
Linda Boloko, MBChB
Email
linda.boloko@gmail.com
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD will be shared on request, after discussion with ethics committee
Learn more about this trial
Testing New Strategies for Patients Hospitalised With HIV-associated Disseminated Tuberculosis
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