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.: PACTR202301805346465 Date of Approval: 19/01/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title panTB-HM
Official scientific title A novel 4-month pan-TB regimen targeting both Host and Microbe (panTB-HM)
Brief summary describing the background and objectives of the trial Tuberculosis is a leading global cause of morbidity and mortality. Even if cured, most patients are left with permanent lung damage that impairs lung function and shortens long-term survival. These concerns are increased many-fold in rifampin-resistant (RIF-R) TB, in which cure is less likely, and long-term outcomes are more profoundly affected. This project will develop the first regimen meeting WHO criteria for a pan-TB indication, ie, without requiring knowledge of RIF susceptibility. The regimen will combine sutezolid (a linezolid analog with a superior therapeutic index and safety profile in phase 1 and 2 trials) with the approved anti-TB drugs bedaquiline and pretomanid. This phase 2c trial will test sutezolid at 2 dose levels to optimise its efficacy and safety. It will also test whether the addition of N-acetylcysteine (NAC), a re-purposed host-directed WHO essential medicine, can protect the lung and liver against oxidative damage, preserve lung function, and accelerate the eradication of MTB infection by replenishing glutathione (GSH). Our modelling indicates this new regimen (SBPN) can be a highly effective intervention, preventing deaths due to treatment failure in patients with RIF-R-TB, and recovering years of life otherwise lost post-TB in all patients by preserving lung function.
Type of trial CCT
Acronym (If the trial has an acronym then please provide) panTBHM
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Tuberculosis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 23/01/2023
Actual trial start date 24/07/2023
Anticipated date of last follow up 30/05/2025
Actual Last follow-up date
Anticipated target sample size (number of participants) 352
Actual target sample size (number of participants)
Recruitment status Closed to recruitment,follow-up continuing
Publication URL https://pantb-hm.org/
Secondary Ids Issuing authority/Trial register
6986 South African National Clinical Trial Registry
RIA2019AMR 2647 European and Developing Countries Clinical Trials Partnership
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 Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification 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
Experimental Group Sutezolid 1200mg QD plus bedaquiline and pretomanid Sutezolid 1200mg QD plus bedaquiline and pretomanid 4 months Arm 1 Sutezolid will be given at a dose of 1200mg QD in arm 1. Bedaquiline and pretomanid will be used at approved doses: bedaquiline at 400mg QD for 14 days, followed by 200mg TIW and pretomanid at 200mg daily. 88
Experimental Group Sutezolid 1600mg QD plus bedaquiline and pretomanid Sutezolid 1600mg QD plus bedaquiline and pretomanid 4 months Arm 2 Sutezolid will be given at a dose of 1600mg QD in arm 2. Bedaquiline and pretomanid will be used at approved doses: bedaquiline at 400mg QD for 14 days followed by 200mg TIW, and pretomanid at 200mg daily. 88
Experimental Group Sutezolid 1600mg QD plus bedaquiline pretomanid and N acetyl cysteine Sutezolid 1600mg QD plus bedaquiline pretomanid and N acetyl cysteine 4 months Arm 3 Sutezolid will be given at a dose of 1600mg QD in arm 3. Bedaquiline and pretomanid will be used at approved doses: bedaquiline at 400mg QD for 14 days, followed by 200mg TIW and pretomanid at 200mg daily. NAC will be given at a dose of 1800mg BID. 88
Control Group 2HRZE and 4HR 2HRZE and 4HR 6 months Arm 4 Patients assigned to the control arm will receive fixed-dose combination tablets of isoniazid, rifampin, ethambutol and pyrazinamide for the first 8 weeks and isoniazid and rifampin tablets subsequently. Dosing will be weight banded according to national guidelines. 88 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Aged 18 to 65 years 2. Willing and able to provide signed written consent prior to undertaking any trial-related procedures. a. Or, in the case of illiteracy, witnessed oral consent 3. Body weight (in light clothing without shoes) between 30 and 90 kg. 4. Radiographic evidence of pulmonary tuberculosis 5. Positive Xpert TB/RIF (original or Ultra) for MTB 6. RIF susceptibility diagnosed by Xpert TB/RIF, with subsequent culture confirmation 7. If sexually active, willing to use an effective contraceptive method for the duration of tuberculosis treatment 8. HIV-1 seronegative, or if HIV-1 seropositive, CD4 T cell count ≥100/µl and either receiving ART or willing to start ART during study participation 9. SARS-CoV-2 PCR or antigen test negative, or if positive, either fully vaccinated against Covid-19 or with D-dimer <0.8 g/ml 10. Willing to adhere to a diet excluding tyramine-rich foods (certain mold-ripened cheeses and cured meats), and to avoid eating grapefruits and pomelos 1. Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments 2. Current or imminent (within 24 hr) treatment for malaria. 3. Pregnant or nursing 4. Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow-up period. 5. TB meningitis or spondylitis, or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator. 6. History of allergy or hypersensitivity to any of the trial therapies or related substances. 7. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial. 8. Prior TB treatment in the preceding 6 months 9. Angina pectoris requiring treatment with nitroglycerin or other nitrates 10. Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator 11. History of unstable Diabetes Mellitus requiring hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening. 12. Use of systemic corticosteroids within the past 28 days. 13. Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitors 14. Patients requiring treatment with antidepressants, including MAO inhibitors and SSRIs. 15. Subjects with any of the following abnormal laboratory values: a. HBsAg positive b. creatinine >2 mg/dL c. hemoglobin <8 g/dL d. platelets <100x109 cells/L e. serum potassium <3.5 mM/L f. alanine aminotransferase (ALT) ≥2.0 x ULN g. alkaline phosphatase (AP) >5.0 x ULN h. total bilirubin >1.5 mg/dL i. random blood glucose >200 mg/dL NB: All of the inclusion and none of the exclusion criteria must be met Adult: 19 Year-44 Year,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 19/12/2022 University of the Witwatersrand Human Research Ethics Committee Medical
Ethics Committee Address
Street address City Postal code Country
31 Princess of Wales Terrace, Parktown Johannesburg 2193 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 26/01/2023 Mbeya Medical Research and Ethics review Committee
Ethics Committee Address
Street address City Postal code Country
Mbeya Zonal Referral Hospital, Hospital Hill Road, P. 0 . Box 419, Mbeya Mbeya 419 United Republic of Tanzania
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 03/07/2023 National Institute for Medical Research
Ethics Committee Address
Street address City Postal code Country
3 Barack Obama Drive 11101 Dar es Salaam Dar es Salaam 11101 United Republic of Tanzania
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 19/09/2023 COMITE NACIONAL DE BIOETICA PARA A SAUDE CNBS
Ethics Committee Address
Street address City Postal code Country
Estrada Nacional Nacional No1 Bairro da Vila Parcela n 3943 Marracuene Mozambique Maputo 258 Mozambique
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome The proportion of patients achieving durable (non-relapsing) cure, assessed after 1 year of post-treatment follow-up. 1 year of post-treatment follow-up
Secondary Outcome Safety 1. The proportion of subjects with TE ALT increases, graded according to severity 2. The proportion of subjects with TE increases in transaminases and bilirubin meeting Hy’s criteria for se-rious liver injury 3. The proportion of subjects with TE AEs, according to seriousness 4. The number of TE AEs per treatment arm, according to seriousness 5. The proportion of subjects requiring temporary or permanent treatment discontinuation due to safety or tolerability concerns Recorded from day 1 through 4 weeks post end-of-treatment
Secondary Outcome Pulmonary function 6. FEV1 and FVC at 1, 2, 6, and 18 months after initiation of treatment 7. FEV1 and FVC slope during 6 and 18 months after initiation of treatment 8. FEV1/FVC ratio at 1, 2, 6, and 18 months after initiation of treatment FEV1 and FVC at 1, 2, 6, and 18 months after initiation of treatment, FEV1 and FVC slope during 6 and 18 months after initiation of treatment and FEV1/FVC ratio at 1, 2, 6, and 18 months after ini
Secondary Outcome Microbiology 9. The proportion of subjects with sputum cultures showing growth of MTB at 1, 2, 3, and 4 months after initiation of treatment 10. The hazard ratio for stable culture conversion through the 4th month of treatment 11. The proportion of subjects with treatment failure 12. The proportion of subjects with relapse Measured at at 1, 2, 3, and 4 months after initiation of treatment
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Tembisa Clinical Trials Research Centre Corner Flint Mazibuko and Rev Namane Drive Tembisa Ekurhuleni 1632 South Africa
Clinical HIV Research Unit Helen Joseph Hospital 1 Perth Road Westdene Johannesburg 2092 South Africa
Clinical HIV Research Unit Durban King DinuZulu Hospital Complex 75 RD Naidu Drive, Durban 4015 South Africa
National Institute for Medical Research Mbeya Medical Research Center Hospital Hill road P.O Box 2410 Mbeya 2410 United Republic of Tanzania
Centro de Investigacao e Treino em Saude da Polana Canico Machava site Machava 3888 Eduardo Mondlane av Machava General Hospital Maputo Mocambique Maputo Mozambique
Centro de Investigacao e Treino em Saude da Polana Cani o Mavalane 2260 FPLM av. Mavalane Health Center Maputo Mocambique Maputo Mozambique
TASK Eden 4 Victoria Street George 6529 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
European and Developing Countries Clinical Trials Partnership Anna van Saksenlaan The Hague 51 2593HW Netherlands
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor The Aurum Institue NPC 29 Queens Road Parktown Johannesburg 2193 South Africa NPO
COLLABORATORS
Name Street address City Postal code Country
National Institute for Medical Research Hospital Hill road Mbeya United Republic of Tanzania
Clinical HIV Research Unit 1 Perth Road Johannesburg 2092 South Africa
Instituto Nacional de Saude Centro de Investigacao e Treino em Saude da Polana Canico National Highway No 1 Maputo Mozambique
Sequella Inc United States 9610 Medical Center Drive Maryland 20850 United States of America
Ludwig Maximilians Universitaet Muenchen Geschwister-Scholl-Platz 1 Munchen 80539 Germany
Stellenbosch University Victoria Street Stellenbosch 7505 South Africa
TB Alliance 40 Wall Street New York 10005 United States of America
Stichting Katholieke Universiteit Radboudumc Netherlands Geert Grooteplein Zuid 10 Nijmegen 6525 Netherlands
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Robert Wallis rwallis@auruminstitute.org +18602716745 29 Queens Road Parktown
City Postal code Country Position/Affiliation
Johannesburg South Africa Chief Scientific Officer
Role Name Email Phone Street address
Scientific Enquiries Robert Wallis rwallis@auruminstitute.org +18602716745 29 Queens Road Parktown
City Postal code Country Position/Affiliation
Johannesburg 2193 South Africa Chief Scientific Officer
Role Name Email Phone Street address
Public Enquiries Don Mudzengi dmudzengi@auruminstitute.org +27105901388 29 Queens Road Parktown
City Postal code Country Position/Affiliation
Johannesburg 2193 South Africa Programme Manager
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes De-identified participant data will be available but accessed upon request and approval. In addition, third parties may obtain study data access upon request and permission of the Steering Group. Study Protocol Data requests can be submitted starting 1 year after article publication, and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis. Controlled access
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
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Anticipated trial start date 16/12/2022 We previously submitted 1 October 2020 as the trial start date because that is the grant commencement date. Between 2020 October and December 2022, we were manufacturing the investigational product, which forms part of the trial, and pre-recruitment. However, participant recruitment will begin in January 2023 and the date has been adjusted accordingly. We have received regulatory approval for the investigational product, Sutezolid in South Africa. We are now waiting for the ethics in South Africa. Mozambique and Tanzania sites submitted after South Africa and they expect to receive their approvals in March and April respectively and begin recruitment in the same month. 01 Oct 2020 23 Jan 2023
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Actual trial start date 16/12/2022 Recruitment has not started. We had previously put the date that the grant commenced. 01 Oct 2020
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Actual trial start date 21/09/2023 Trial now recruiting 24 Jul 2023
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 21/09/2023 Trial now recruiting Not yet recruiting Recruiting
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 18/03/2025 Closed for accrual Recruiting Closed to recruitment,follow-up continuing
Section Name Field Name Date Reason Old Value Updated Value
Study Design Intervention assignment 09/01/2023 Correction Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously Parallel: different groups receive different interventions at same time during study
Section Name Field Name Date Reason Old Value Updated Value
Study Design Masking type 09/01/2023 Correction Masking/blinding used Open-label(Masking Not Used)
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 21/09/2023 Newly approved site in South Africa Clinical HIV Research Unit Durban, King DinuZulu Hospital Complex 75 RD Naidu Drive,, Durban, 4015, South Africa
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 21/09/2023 Newly approved site in Tanzania National Institute for Medical Research Mbeya Medical Research Center, Hospital Hill road P.O Box 2410, Mbeya, 2410, United Republic of Tanzania
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 14/05/2024 Site fully approved and recruiting Centro de Investigacao e Treino em Saude da Polana Canico Machava site, Machava 3888 Eduardo Mondlane av Machava General Hospital Maputo Mocambique, Maputo, , Mozambique
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 14/05/2024 Site fully approved and now recruiting Centro de Investigacao e Treino em Saude da Polana Cani o, Mavalane 2260 FPLM av. Mavalane Health Center Maputo Mocambique, Maputo, , Mozambique
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 14/05/2024 Site fully approved and recruiting TASK Eden, 4 Victoria Street, George, 6529, South Africa
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 09/01/2023 Uploading ethics approval in South Africa FALSE, University of the Witwatersrand Human Research Ethics Committee Medical, 31 Princess of Wales Terrace, Parktown, Johannesburg, 2193, South Africa, 07 Sep 2022, , +27112749281, HREC-Medical.ResearchOffice@wits.ac.za, FALSE, University of the Witwatersrand Human Research Ethics Committee Medical, 31 Princess of Wales Terrace, Parktown, Johannesburg, 2193, South Africa, 07 Sep 2022, , +27112749281, HREC-Medical.ResearchOffice@wits.ac.za, 24206_20956_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 09/01/2023 Uploading ethics approval FALSE, University of the Witwatersrand Human Research Ethics Committee Medical, 31 Princess of Wales Terrace, Parktown, Johannesburg, 2193, South Africa, 07 Sep 2022, , +27112749281, HREC-Medical.ResearchOffice@wits.ac.za, 24206_20956_4737.pdf TRUE, University of the Witwatersrand Human Research Ethics Committee Medical, 31 Princess of Wales Terrace, Parktown, Johannesburg, 2193, South Africa, 07 Sep 2022, 19 Dec 2022, +27112749281, HREC-Medical.ResearchOffice@wits.ac.za, 24206_20956_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 21/09/2023 Initial approval in Tanzania TRUE, Mbeya Medical Research and Ethics review Committee, Mbeya Zonal Referral Hospital, Hospital Hill Road, P. 0 . Box 419, Mbeya, Mbeya, 419, United Republic of Tanzania, , 26 Jan 2023, +2552503456, info@mzrh.go.tz, 24206_25812_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 21/09/2023 National ethics in Tanzania now received TRUE, National Institute for Medical Research, 3 Barack Obama Drive 11101 Dar es Salaam, Dar es Salaam, 11101, United Republic of Tanzania, , 03 Jul 2023, +255222121400, ethics@nimr.or.tz, 24206_25813_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 14/05/2024 Adding ethics approval certificate. TRUE, COMITE NACIONAL DE BIOETICA PARA A SAUDE CNBS , Estrada Nacional Nacional No1 Bairro da Vila Parcela n 3943 Marracuene Mozambique, Maputo, 258, Mozambique, , 19 Sep 2023, 0025821431103, info@ins.gov.mz, 24206_29532_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD description 16/12/2022 Correction During the Project, each Party is involved in collecting data in the form of reports and technical documentation. Each Party shall properly store and maintain collected data. All Data generated from the Project will be centrally complied with, managed, coordinated and maintained by LMU. LMU hereby undertakes to maintain the Project electronic archive for the duration of the Project and for a period of at least 10 years after the end of the Project. The appointed Principal Investigator (PI) for each Party shall ensure that all Data is submitted to LMU. All Data generated from the Project is owned by the Party which has developed it and will be made available to members of the Consortium according to prespecified objectives and research questions outlined in the Protocol. Third parties may obtain access to study Data upon request and permission of the Steering Group. Each respective Party is responsible for preparing, submitting and approving a Data Transfer Agreement (DTA) according to national regulations. The Data shall be stored for at least the complete duration of the Consortium. Ownership of Results shall follow the specifications of Article 26 of the Grant Agreement. A Joint Ownership Agreement between Sequella and Aurum (as Coordinator) will describe how Results related to the combination of sutezolid plus N-acetylcysteine will be shared. Clinical sample ownership, storage and maintenance Clinical samples will be stored at the study site according to the respective national Biobank regulations. Members of the Consortium can gain access to those samples according to the prespecified objectives and research questions outlined in the Protocol. Third parties may obtain access to samples upon request and permission of the Trial Executive Committee. De-identified participant data will be available but accessed upon request and approval. In addition, third parties may obtain study data access upon request and permission of the Steering Group.
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD description 16/12/2022 Correction De-identified participant data will be available but accessed upon request and approval. In addition, third parties may obtain study data access upon request and permission of the Steering Group. De-identified participant data will be available but accessed upon request and approval. In addition, third parties may obtain study data access upon request and permission of the Steering Group.
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD-Sharing time frame 16/12/2022 Correction Time frames will are still to be determined by the Trial Executive committee. A data sharing agreement will be in place to govern data sharing during the course of the study. Data requests can be submitted starting 1 year after article publication, and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
Section Name Field Name Date Reason Old Value Updated Value
Reporting Key access criteria 16/12/2022 Correction Third parties may obtain access to study Data upon request and permission of the Steering Group. Each respective Party is responsible for the preparation, submission and approval of a Data Transfer Agreement (DTA) according to each respective national regulations. The Data shall be stored for at least the complete duration of the Consortium. Ownership of Results shall follow the specifications of Article 26 of the Grant Agreement. A Joint Ownership Agreement between Sequella and Aurum (as Coordinator) will describe how Results related to the combination of sutezolid plus N-acetylcysteine will be shared. Clinical sample ownership, storage and maintenance Clinical samples will be stored at the study site according to the respective national Biobank regulations. Members of the Consortium can gain access to those samples according to the prespecified objectives and research questions outlined in the Protocol. Third parties may obtain access to samples upon request and permission of the Trial Executive Committee. Controlled access