Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM

Brief Title

Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM

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

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).
    

Detailed Description

      HIV-1 infected adults with newly-diagnosed TBM (n = 100) will be recruited from four
      public-sector hospitals in Cape Town and Port Elizebeth, South Africa. Participants will be
      randomised across two experimental (n = 30 each) and one standard of care (n = 40) arms.
      Treatment will be provided in all arms for 56 days, after which participants will be referred
      back to public sector facilities to complete standard therapy for HIV-associated TBM.

      The primary objective of the study is to investigate the safety of enhanced antimicrobial
      therapy including increased dose RIF and LZD with or without adjunctive aspirin added to
      standard therapy for TBM in HIV-1 infected adults.

      Secondary objectives are;

        1. To determine cerebrospinal fluid M.tb culture positivity and Gene Xpert® Ultra
           positivity at baseline and at 3 and 28 days post treatment by allocation.

        2. To evaluate the effect of aspirin and enhanced tuberculosis treatment on the incidence
           of immune reconstitution syndrome in participants starting antiretroviral therapy.

        3. To evaluate the effect of high dose rifampicin and linezolid, with and without aspirin
           on the transcriptional signature derived from whole blood and cerebrospinal fluid RNA
           sequencing, as well as the metabolomic and proteomic profiles, in tuberculous
           meningitis.

        4. To evaluate the effect of high dose rifampicin and linezolid with and without aspirin on
           central nervous system imaging in conjunction with clinical, immunological and
           transcriptional profiling.

        5. To store biological samples for future analysis of potential biomarkers of treatment
           efficacy and/or novel diagnostic assays.

        6. To determine i) whether host genotype, including LTA4H genotype, influences therapeutic
           effect of aspirin in HIV-TBM and ii) the pharmacogenetic influence on rifampicin and
           linezolid exposures and toxicity.

      All participants will receive antitubercular chemotherapy and corticosteroids as standard of
      care as per national South African guidelines. Participants allocated to experimental arms 2
      and 3 will receive additional rifampicin (total oral dose 35 mg/kg/day) plus oral linezolid
      1200mg daily for the first 28 days, reduced to 600 mg daily for the next 28 days. Those
      randomized to experimental arm 3 will also receive oral aspirin 1000 mg daily.

      All consenting LASER-TBM participants in experimental arms (n = 60) will undergo a second
      randomisation to receive either oral (35mg/kg) or IV (20mg/kg) rifampicin at the time of
      study entry. This sub-study is powered to demonstrate bioequivalence at day 3 of
      administration, after which all participants will be continued on oral rifampicin dosed at
      35mg/kg.

      Trial participation will be for 180 days post-randomization: primary safety endpoints and
      secondary efficacy endpoints will be evaluated at day 56; additional secondary endpoints will
      be evaluated at day 180.

      There are seven scheduled study visits. The first six of thee will occur within the first 56
      days, with an additional structured interview at 6 months. All visits will involve a clinical
      assessment including specified clinical outcome measures to assess functional and cognitive
      disability. Phlebotomy will be performed at study visits within the first 56 days to monitor
      for pre-specified parameters of drug safety (haematology, biochemistry) as well as to collect
      blood for downstream transcriptomic, proteomic and metabolomic analysis. Lumbar puncture will
      take place at day 3 and day 28. Cerebrospinal fluid will be analysed for Mycobacterium
      tuberculosis culture and Gene Xpert® Ultra cycle threshold values. Cerebrospinal fluid (CSF)
      will be stored for downstream transcriptomic, proteomic and metabolomic analysis. Baseline
      and day 56 brain imaging will be performed in all study participants.

      All enrolled participants will undergo sparse plasma PK sampling at the Day 28 and Day 56
      visits.

      Cerebrospinal fluid (CSF) will be collected from all participants for determination of
      linezolid and rifampicin concentrations on Days 3 and 28. The timing of the Day 3 lumbar
      puncture will be randomised to intervals of 1 - 3, 3 - 6, 6 - 10, and 24 hours after observed
      antitubercular drug dosing in order to construct a concentration-time profile for the
      population. A single sample will be collected at each time interval. A second lumbar puncture
      will take place at the Day 28 visit, to coincide with the 4-hour plasma PK sample.

      All participants (n=100) will be offered participation in the intensive sampling component of
      the PK sub-study at the time of randomization to the main study. Intensive plasma sampling
      will take place at the Day 3 study visit. Serial venous blood samples will be collected
      through a peripheral intravenous catheter pre-dose, and at 0.5, 1, 2, 3, 6, 8 - 10, and 24
      hours after witnessed drug intake and an overnight fast. Sparse sampling will be performed at
      Day 3 for participants who decline intensive sampling or in whom this fails.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of participants in each arm who develop treatment related adverse events (AEs).

Secondary Outcome

 Death and disability after 56 days on treatment.

Condition

Tuberculosis Meningitis

Intervention

Linezolid

Study Arms / Comparison Groups

 Standard of care anti-tubercular therapy
Description:  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)).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

100

Start Date

June 12, 2019

Completion Date

December 31, 2020

Primary Completion Date

December 30, 2020

Eligibility 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Robert J Wilkinson, PhD, +27727633386, [email protected]

Location Countries

South Africa

Location Countries

South Africa

Administrative Informations


NCT ID

NCT03927313

Organization ID

LASER-TBM


Responsible Party

Principal Investigator

Study Sponsor

University of Cape Town


Study Sponsor

Robert J Wilkinson, PhD, Principal Investigator, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town


Verification Date

August 2020