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Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM (LASER-TBM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03927313
Recruitment Status : Recruiting
First Posted : April 25, 2019
Last Update Posted : August 14, 2020
Sponsor:
Information provided by (Responsible Party):
Robert J Wilkinson, University of Cape Town

Brief Summary:

LASER-TBM is a parallel group, randomized, multi-arm phase IIa trial evaluating the safety of increased dose rifampicin (RIF) plus linezolid (LZD), with or without aspirin (ASA), for the treatment of HIV-infected adults with tuberculous meningitis (TBM). The study will recruit 100 HIV-infected adults with TBM across four sites in South Africa.

The primary endpoint is the occurrence of solicited treatment-related adverse events.

Secondary endpoints include death and disability (including neurocognitive impairment), radiological outcomes, and the occurrence of immune reconstitution inflammatory syndrome (IRIS).

A nested pharmacokinetic (PK) substudy aims to:

  1. Describe the plasma and cerebrospinal fluid (CSF) PK of LZD and high dose RIF.
  2. Evaluate the relationship between drug exposures, toxicity and efficacy.
  3. Compare exposures between intravenous and oral RIF administration.
  4. Investigate the impact of high dose RIF on LZD and dolutegravir (DTG).

Condition or disease Intervention/treatment Phase
Tuberculosis Meningitis HIV-1-infection Drug: Linezolid Drug: High dose rifampicin Drug: Aspirin Drug: Standard of Care anti-tuberculous therapy Drug: Dexamethasone Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase IIA, randomized, active-controlled, open label, parallel-group trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase IIA Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid With or Without Aspirin, for HIV-associated Tuberculous Meningitis
Actual Study Start Date : June 12, 2019
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Active Comparator: Standard of care anti-tubercular therapy
Standard of care anti-TB treatment. (10 mg/kg oral rifampicin, 5 mg/kg oral isoniazid, 15 mg/kg oral ethambutol and 25 mg/kg oral pyrazinamide daily for 2 months as fixed dose combination tablets (followed by 10 mg/kg oral rifampicin and 5 mg/kg isoniazid daily for 4-7 months in routine care after study completed)).
Drug: Standard of Care anti-tuberculous therapy
10mg/kg oral rifampicin, 5mg/kg oral isoniazid, 15mg/kg oral ethambutol, 25mg/kg oral pyrazinamide daily for 56 days.

Drug: Dexamethasone
Dexamethasone according to doses of Thwaites criteria for the first 8 weeks of anti-tuberculous treatment. Doses differ according to participants Medical Research Council (MRC) grade. Given orally if participant can swallow and intravenously if they cannot.

Experimental: Intensified anti-tubercular therapy

Standard of care anti-TB therapy as described in Arm 1,

Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days).

Drug: Linezolid
For both experimental arms: 1.2g linezolid 28 days, followed by 600mg linezolid for 28 days

Drug: High dose rifampicin
For both experimental arms: additional 25mg/kg (making a total of 35mg/kg) rifampicin, for the first 56 days of treatment

Drug: Standard of Care anti-tuberculous therapy
10mg/kg oral rifampicin, 5mg/kg oral isoniazid, 15mg/kg oral ethambutol, 25mg/kg oral pyrazinamide daily for 56 days.

Drug: Dexamethasone
Dexamethasone according to doses of Thwaites criteria for the first 8 weeks of anti-tuberculous treatment. Doses differ according to participants Medical Research Council (MRC) grade. Given orally if participant can swallow and intravenously if they cannot.

Experimental: Intensified anti-tubercular therapy plus aspirin

Standard of care anti-TB therapy as described in Arm 1,

Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days),

Plus aspirin (1000mg orally daily for the first 56 days of Tuberculous Meningitis treatment)

Drug: Linezolid
For both experimental arms: 1.2g linezolid 28 days, followed by 600mg linezolid for 28 days

Drug: High dose rifampicin
For both experimental arms: additional 25mg/kg (making a total of 35mg/kg) rifampicin, for the first 56 days of treatment

Drug: Aspirin
For only one of the experimental arms: 1000mg of aspirin daily for 56 days.

Drug: Standard of Care anti-tuberculous therapy
10mg/kg oral rifampicin, 5mg/kg oral isoniazid, 15mg/kg oral ethambutol, 25mg/kg oral pyrazinamide daily for 56 days.

Drug: Dexamethasone
Dexamethasone according to doses of Thwaites criteria for the first 8 weeks of anti-tuberculous treatment. Doses differ according to participants Medical Research Council (MRC) grade. Given orally if participant can swallow and intravenously if they cannot.




Primary Outcome Measures :
  1. Number of participants in each arm who develop treatment related adverse events (AEs). [ Time Frame: 56 days ]
    The amount of participants who develop any of the following treatment related adverse events by the time they have been on treatment for 56 days will be counted: Peripheral neuropathy, optic neuropathy, anaemia, neutropaenia, thrombocytopaenia, upper gastro-intestinal haemorrhage, intracerebral haemorrhage, drug-induced liver injury.


Secondary Outcome Measures :
  1. Death and disability after 56 days on treatment. [ Time Frame: 56 days ]
    A comparison will be made of the proportion of participants in each arm who died, and their grade of disability will be compared according to Modified Rankin Scoring.

  2. Death at day 56 and day 180. [ Time Frame: 180 days ]
    In all arms: the number of participants who have died at Day 56 will be compared to those that have died at Day 180.

  3. Number of participants who are disabled. [ Time Frame: 180 days ]
    Comparison of level of disability of participants at 56 and 180 days, stratifying by Medical Research Council grade.

  4. Number of participants who develop Grade 3 or Grade 4 adverse events (AEs). [ Time Frame: 56 days ]
    In all 3 arms: comparison of the number of participants who develop Grade 3 or Grade 4 adverse events (according to Division of AIDS (DAIDS) criteria) by the time they have been on treatment or 56 days.

  5. Number of participants in whom experimental drugs had to be stopped. [ Time Frame: 56 days ]
    At 56 days on treatment, the number of participants in the experimental arms in whom rifampicin, linezolid and/or aspirin had to be stopped.

  6. Linezolid toxicity [ Time Frame: 56 days ]
    To note the presence of the following adverse events in all participants in the experimental arms: peripheral neuropathy, optic neuropathy, anaemia, neutropaenia, thrombocytopaenia and hyperlactataemia.

  7. Major bleeding events. [ Time Frame: 180 days ]
    To note at 6 months, the amount of participants who develop upper gastro-intestinal or intra-cerebral haemorrhage after receiving 1000mg daily aspirin as part of the trial.

  8. Cerebrospinal fluid culture conversion. [ Time Frame: Day 28 and day 56 ]
    To compare in the different arms, between lumbar punctures done at day 3 and day 28, the time to automated liquid culture positivity and Gene-Xpert ultra threshold values (for mycobacterium tuberculosis) of cerebrospinal fluid.

  9. The occurrence of TBM-immune reconstitution inflammatory syndrome [ Time Frame: 56 days ]
    The amount of participants in all 3 arms who develop paradoxical tuberculosis immune reconstitution, as defined by th modified INSHI criteria.

  10. Changes on brain imaging [ Time Frame: Day 56 ]
    To compare at day 56, in participants who had brain imaging at baseline, changes in brain imaging at day 56.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 seropositivity by rapid test, confirmed by enzyme-linked immunosorbent assay (regardless of Antiretroviral Therapy (ART) status);
  • Age 18 years or older;
  • Tuberculous meningitis defined as 'possible', 'probable' or 'definite' as per published case definitions

Exclusion Criteria:

  • Rifampicin-resistant M. tb detected in any microbiological specimen;
  • History of allergy or hypersensitivity to H, E, R and Z, LZD or ASA;
  • Received more than 5 days of antitubercular therapy in the 30 days prior to screening;
  • Received a dose of ASA or any other NSAID within 2 weeks of screening;
  • CSF unobtainable by lumbar puncture or another procedure;
  • Evidence of bacterial or cryptococcal meningitis;
  • Severe concurrent uncontrolled opportunistic infection including but not limited to active cytomegalovirus-associated disease, Kaposi sarcoma, Pneumocystis jirovecii pneumonia, HIV related or unrelated malignancy or gastrointestinal bleeding;
  • Any other form of immunosuppressive therapy including antineoplastic and biologic agents apart from corticosteroids;
  • Is pregnant in the third trimester;
  • Peripheral neuropathy scoring Grade 3 or above on Brief Peripheral Neuropathy Score
  • Any disease or condition in which the use of the standard TB drugs or any of their components is contraindicated, including but not limited to allergy to any TB drug or their components;
  • The presence of one or more of the following:

    • Estimated glomerular filtration rate (eGFR) < 20ml/min/1.73m2 (using the Cockcroft-Gault equation)
    • International normalised ration (INR) > 1.4 and/or clinical evidence of liver failure or decompensated cirrhosis
    • Hemoglobin < 8.0 g/dL
    • Platelets < 50 x109 /L
    • Neutrophils < 0.5 x 109 cells/L;
  • The patient has any disease or condition in which any of the medicinal products listed in the section pertaining to prohibited medication is used and cannot be safely stopped;
  • The patient has a known or suspected, current or history of drug abuse, within the past 2 years, that is, in the opinion of the investigators, sufficient to compromise the safety or cooperation of the patient.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03927313


Contacts
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Contact: Nompumelelo Maxebengula, Bcom +27727633386 ext +27727633386 mpumi.maxebengula@uct.ac.za
Contact: Stephani Botha, Dr +27722006020 ext +27727633386 stephani.botha@uct.ac.za

Locations
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South Africa
Livingstone Hospital Not yet recruiting
Port Elizabeth, Eastern Cape, South Africa, 6020
Contact: Nompumelelo Maxebengula, Bcom    +27727633386    mpumi.maxebengula@uct.ac.za   
Contact: Stephani Maxebengula, Dr    +27722006020    stephani.botha@uct.ac.za   
Principal Investigator: John Black, MBChB         
Sub-Investigator: Agharad G Davis, Dr         
Mitchells Plain Hospital Recruiting
Cape Town, Western Cape, South Africa, 7786
Contact: Nompumelelo Maxebengula, Bcom    +27727633386    mpumi.maxebengula@uct.ac.za   
Contact: Stephani Botha, Dr    +27722006020    stephani.botha@uct.ac.za   
Principal Investigator: Graeme Meintjes, PHD         
Sub-Investigator: Thomas Crede, Dr         
Groote Schuur Hospital Recruiting
Cape Town, Western Cape, South Africa, 7925
Contact: Nompumelelo Maxebengula, Bcom    +27727633386    mpumi.maxebengula@uct.ac.za   
Contact: Stephani Botha, Dr    +27722006020    stephani.botha@uct.ac.za   
Principal Investigator: Rorbet J Wilkinson, PHD         
Sub-Investigator: Angharad G Davis, Dr         
New Somerset Hospital Recruiting
Cape Town, Western Cape, South Africa, 8001
Contact: Nompumelelo Maxebengula, Bcom    +27727633386    mpumi.maxebengula@uct.ac.za   
Contact: Stephani Botha, Dr    +27722006020    stephani.botha@uct.ac.za   
Principal Investigator: Sean Wasserman, MMed         
Sub-Investigator: Muhammed S Moosa, Dr         
Sub-Investigator: Yakoob Vallie, Dr         
Sponsors and Collaborators
University of Cape Town
Investigators
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Principal Investigator: Robert J Wilkinson, PhD Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town
Principal Investigator: Sean Wasserman, MMed Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town
Principal Investigator: Graeme Meintjes, PhD Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town
Principal Investigator: John Black, MBChB Department of Medicine, University of Cape Town and Walter Sisal University
Study Chair: Angharad G Davis, Dr 1. Faculty of Life Sciences, University College London, UK 2. Department of Medicine, University of Cape Town, Observatory 7925, Republic of South Africa
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Responsible Party: Robert J Wilkinson, National Principal Investigator, University of Cape Town
ClinicalTrials.gov Identifier: NCT03927313    
Other Study ID Numbers: LASER-TBM
First Posted: April 25, 2019    Key Record Dates
Last Update Posted: August 14, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Robert J Wilkinson, University of Cape Town:
TB meningitis, HIV
Additional relevant MeSH terms:
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Tuberculosis
Meningococcal Infections
Tuberculosis, Meningeal
Meningitis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Central Nervous System Diseases
Nervous System Diseases
Neisseriaceae Infections
Gram-Negative Bacterial Infections
Meningitis, Bacterial
Central Nervous System Bacterial Infections
Tuberculosis, Central Nervous System
Central Nervous System Infections
Aspirin
Rifampin
Linezolid
Dexamethasone
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal