Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR201902921101705 Date of Approval: 27/02/2019
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title ‘LASER-TBM’ Linezolid, ASpirin and Enhanced dose Rifampicin in HIV-TBM
Official scientific title Phase IIA Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolic, with or without, for HIV-Associated Tuberculous Meningitis
Brief summary describing the background and objectives of the trial PRIMARY OBJECTIVE To investigate the safety of enhanced antimicrobial therapy including increased dose RIF and LZD with or without adjunctive ASA added to standard therapy for TBM in HIV-1 infected adults. SECONDARY OBJECTIVES 1. To determine CSF 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 ASA and enhanced TB treatment on the incidence of IRIS in participants starting ART; 3. To evaluate the effect of high dose RIF and LZD with and without ASA on the transcriptional signature derived from whole blood and CSF RNA sequencing, as well as the metabolomic and proteomic profiles, in TBM; 4. To evaluate the effect of high dose RIF and LZD with and without ASA on CNS 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 ASA in HIV-TBM and ii) pharmacogenetic influence on RIF and LZD exposures and toxicity; 7. In a pharmacokinetic (PK) sub-study: Describe the plasma and CSF PK of LZD and high dose RIF, Evaluate the relationship between drug exposures and toxicity and efficacy, Investigate the impact of high dose RIF on LZD and dolutegravir (DTG) exposures, compare exposure between intravenous and oral RIF administration
Type of trial RCT
Acronym (If the trial has an acronym then please provide) LASER TMB
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied HIV/AIDS,Tuberculous meningitis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/04/2019
Actual trial start date 12/06/2019
Anticipated date of last follow up 31/01/2021
Actual Last follow-up date
Anticipated target sample size (number of participants) 100
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Arm 1 Standard Antitubercular Therapy 10 mg/kg oral RIF, 5 mg/kg oral INH, 15 mg/kg oral EMB and 25 mg/kg oral PZA O.D. for 2 months (followed by 10 mg/kg oral RIF and 5 mg/kg INH O.D. for 4-7 months in routine care at clinician discretion). 56 days Treatment with normal dose RHZE 40 Active-Treatment of Control Group
Experimental Group Arm 2 Intensified Antitubercular Therapy and LZD 10 mg/kg oral RIF, 5 mg/kg oral INH, 15 mg/kg oral EMB and 25 mg/kg oral PZA O.D. for 2 months (followed by 10 mg/kg oral RIF and 5 mg/kg INH O.D. for 4-7 months in routine care at clinician discretion). Plus additional 25 mg/kg RIF (total dose RIF 35 mg/kg orally for the first 56 days of treatment) and LZD ( 1,200 mg orally O.D. for first 28 days reduced to 600 mg O.D. for next 28 days). 56 days: Rif 35mg/kg dly INH 5mg/kg dly EMB 15mg/kg dly PZA 25mg/kg dly LZD 1200mg dly for 28 days then 600mg dly for 28 days. High dose Rifampicin and adjunctive Linezolid 30
Experimental Group Arm 3 Intensified Antitubercular Therapy and LZD and ASA 10 mg/kg oral RIF, 5 mg/kg oral INH, 15 mg/kg oral EMB and 25 mg/kg oral PZA O.D. for 2 months (followed by 10 mg/kg oral RIF and 5 mg/kg INH O.D. for 4- 7 months in routine care at clinician discretion). Plus additional 25 mg/kg RIF (total dose RIF 35 mg/kg orally for the first 56 days of treatment) and LZD ( 1,200 mg orally O.D. for first 28 days reduced to 600 mg O.D. for next 28 days) and ASA (1000mg orally O.D. for the first 56 days of TBM treatment) Arm3: Rif 35mg/kg dly INH 5mg/kg dly EMB 15mg/kg dly PZA 25mg/kg dly LZD 1200mg dly for 28 days then 600mg dly for 28 days ASA 1000 mg dly High dose Rifampicin and adjunctive Linezolid with Aspirin 30
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
HIV-1 seropositivity by rapid test, confirmed by enzyme-linked immunosorbent assay (regardless of ART status); Age 18 years or older; Tuberculous Meningitis defined as ‘possible’, ‘probable’ or ‘definite’ as per the published case definition[68] 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 (section xx) 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 Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 65 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 21/01/2019 University of Cape Town Faculty of Health Sciences Human Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Room E53-46 Old Building, Groote Schuur Hospital, Observatory Cape Town 7925 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 11/10/2018 Faculty of Health UCT
Ethics Committee Address
Street address City Postal code Country
Room E53-46 Old Main Building, Groote Schuur Hospital Cape Town 7925 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 30/04/2019 Faculty of Health Science Walter Sisulu University
Ethics Committee Address
Street address City Postal code Country
Academic Health Service Complex of the Eastern Cape, Post Graduate Education and Training, Faculty of Health Sciences, Walter Sisulu University, P/Bag X1, 5117, E.C Umthatha 5117 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome The incidence of solicited treatment-related AEs and death at 56 days associated with increased dose RIF plus LZD with or without adjunctive ASA, when administered alongside standard antitubercular Day 56
Secondary Outcome 1. Death (MRS 6) and disability (MRS 5)   Day 56
Secondary Outcome 2. Death day 56 and Day 180
Secondary Outcome 3. Disability, stratified by baseline MRC grade. Day 56 and Day 180
Secondary Outcome 4. Grade 3 or 4 AE. Day 56
Secondary Outcome 5. Permanent discontinuation of experimental drugs. Day 56
Secondary Outcome 6. Severity and frequency of haematologic and neurologic AE and hyperlactataemia related to LZD use. Day 56
Secondary Outcome 7. Severity and frequency of major bleeding (gastrointestinal and intracerebral) related to ASA use. Day 56
Secondary Outcome 8. M. tb culture status and time to positivity in automated liquid culture (MGIT) and Gene Xpert® Ultra cycle threshold (Ct) values Day 28 and Day 56
Secondary Outcome 9. The occurrence of TBM-IRIS assessed by the modified INSHI criteria [17]. Day 56
Secondary Outcome 10. MRI and CT changes Day 56
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Groote Schuur Hospital Main Road, Observatory Cape Town 7925 South Africa
Michells Plain Hospital 8 A Z Berman Drive, Lentegeur Cape Town 7786 South Africa
New Somerset Hospital Bay Court, Portswood Road, Green Point Cape Town 8001 South Africa
Dora Nginza Hospital Spondo St, New Brighton Port Elizabeth 6059 South Africa
Livingstone Hospital Standford Road, Korsten Port Elizabeth 6020 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Wellcome Trust University of Cape Town Welcome Centre for Infectious Diseases Research in Africa, Faculty of Health Science, University of Cape Town, Anzio Road, Observatory Cape Town 7925 South Africa
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Wellcome Trust University of Cape Town Welcome Centre for Infectious Diseases Research in Africa, Faculty of Health Science, University of Cape Town, Anzio Road, Observatory Cape Town 7925 South Africa University
COLLABORATORS
Name Street address City Postal code Country
Lori Dodd National Institute of Allergies and Infectious Diseases, Bethesda, MD Bethesda United States of America
Maia Lesosky University of Cape Town, CIDRI Africa Cape Town 7925 South Africa
CONTACT PEOPLE
Role Name Email Phone Street address
Public Enquiries Stephani Botha stephani.botha@uct.ac.za +27214066084 Welcome Centre for Infectious Diseases Research in Africa, Room 3.03.5 Wolfson Building, Faculty of Health Science, University of Cape Town, Anzio Road, Observatory
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Research Medical Officer
Role Name Email Phone Street address
Public Enquiries Angharad Grace Davis angharad.davis@uct.ac.za +2761658826 Welcome Centre for Infectious Diseases Research in Africa, Room 3.03.5 Wolfson Building, Faculty of Health Science, University of Cape Town, Anzio Road, Observatory
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Lead Investigator
Role Name Email Phone Street address
Principal Investigator Robert J Wilkinson robert.wilkinson@uct.ac.za +27214066084 Wellcome Centre for Infectious Diseases in Africa, Room 3.03.5, Wolfon Pavilion, Faculty of Health Science, University of Cape Town, Anzio Road Observatory
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Director at CIDRI Africa
Role Name Email Phone Street address
Scientific Enquiries Sean Wasserman sean.wasserman@uct.ac.za +27214066700 Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, CIDRI-Afrika, Institute if Infectious Disease and Molecular Medicine
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Senior Lecture
Role Name Email Phone Street address
Principal Investigator John Black docjohnblack@gmail.com +27833780911 Standford Road, Korsten, Port Elizabeth
City Postal code Country Position/Affiliation
Port Elizabeth 6020 South Africa Site Principal Investigator
Role Name Email Phone Street address
Public Enquiries Marise De Ridder marise.deridder@gmail.com +27827460418 Port Elizabeth Provinvial Hospital, Standford Road, Port Elizabeth, 6020
City Postal code Country Position/Affiliation
Port Elizabeth 6020 South Africa Research Medical Officer
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
No
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information